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Hogan, Brigid L. M.

Overview:

1. Genetic regulation of embryo development using the mouse as a research model.
2. The role of genes and signaling pathways in directing and co-ordinating the development of the lung.
3. The identity and regulation of the different stem cells in the adult lung and their role in repair, fibrosis and cancer.

Positions:

George Barth Geller Professor

Cell Biology
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Professor in Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chair, Department of Cell Biology

Cell Biology
School of Medicine

Education:

Ph.D. 1968

Ph.D. — University of Cambridge (UK)

Src Studentship,

University of Cambridge (UK)

Ph.D. Student,

University of Cambridge (UK)

Postdoc,

University of Sussex (UK)

Postdoc,

Massachusetts Institute of Technology

News:

Grants:

Epithelial-mesenchymal crosstalk in lung fibrosis and alveolar homeostasis

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
Burroughs Wellcome Fund
Role
Mentor
Start Date
September 01, 2014
End Date
August 31, 2020

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

The role of Pdgfra+ fibroblasts in lung fibrosis and alveolar homeostasis

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 05, 2014
End Date
April 30, 2019

Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 01, 2015
End Date
August 31, 2018

Progenitor Cells in Lung Development and Repair

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 05, 1992
End Date
February 28, 2018

An Integrated Approach to Airway Epithelial Repair and Regeneration

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2012
End Date
December 31, 2017

Center for Molecular & Cellular Studies of Ped Disease

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 11, 2003
End Date
November 30, 2017

Training Program in Developmental and Stem Cell Biology

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 01, 2001
End Date
October 31, 2017

Testing novel models of glucocorticoid-induced transcription regulation

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2015
End Date
September 02, 2016

Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 01, 2014
End Date
August 31, 2016

The Duke Multidisciplinary Training Program in Pediatric Lung Disease

Administered By
Pediatrics, Pulmonary and Sleep Medicine
AwardedBy
National Institutes of Health
Role
Faculty Member
Start Date
September 01, 2010
End Date
August 31, 2016

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

Epigenetic Regulation of Intestinal Inflammation

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
December 01, 2013
End Date
June 30, 2015

Multidisciplinary Neonatal Training Grant

Administered By
Pediatrics, Neonatology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2010
End Date
June 30, 2015

Cell Biology of Airway Epithelial Basal Cell Progenitors

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 14, 2010
End Date
July 13, 2011

The Role of transcription factor Sox2 in the homeostasis of the adult esophagus

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2010
End Date
September 30, 2010

Role of BMP Antagonism in Craniofacial and Foregut Development

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
April 01, 2000
End Date
July 31, 2010

BMP Signaling in Lung Development and Postnatal Repair

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2005
End Date
February 28, 2009

Role of Sfrp2 in Cardiac Regeneration

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
December 01, 2006
End Date
November 30, 2007
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Awards:

Respiration Section Awards/Julius H. Comroe, Jr. Distinguished Lecture. American Physiological Society.

Type
National
Awarded By
American Physiological Society
Date
January 01, 2007

Members/ Foreign Associates. National Academy of Science.

Type
National
Awarded By
National Academy of Science
Date
January 01, 2005

Fellows and Foreign Members. Royal Society, The.

Type
National
Awarded By
Royal Society, The
Date
January 01, 2001

Fellows. American Academy of Arts and Sciences.

Type
National
Awarded By
American Academy of Arts and Sciences
Date
January 01, 2001

Member. Institute of Medicine of The National Academies.

Type
National
Awarded By
Institute of Medicine of The National Academies
Date
January 01, 1996

Investigator/Alumni Investigator. Howard Hughes Medical Institute.

Type
National
Awarded By
Howard Hughes Medical Institute
Date
January 01, 1993

Publications:

BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.

The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.

Authors
Tadokoro, T; Gao, X; Hong, CC; Hotten, D; Hogan, BLM
MLA Citation
Tadokoro, T, Gao, X, Hong, CC, Hotten, D, and Hogan, BLM. "BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors." Development (Cambridge, England) 143.5 (March 2016): 764-773.
PMID
26811382
Source
epmc
Published In
Development (Cambridge)
Volume
143
Issue
5
Publish Date
2016
Start Page
764
End Page
773
DOI
10.1242/dev.126656

GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells.

Pseudostratified airway epithelium of the lung is composed of polarized ciliated and secretory cells maintained by basal stem/progenitor cells. An important question is how lineage choice and differentiation are coordinated with apical-basal polarity and epithelial morphogenesis. Our previous studies indicated a key integrative role for the transcription factor Grainyhead-like 2 (Grhl2). In this study, we present further evidence for this model using conditional gene deletion during the regeneration of airway epithelium and clonal organoid culture. We also use CRISPR/Cas9 genome editing in primary human basal cells differentiating into organoids and mucociliary epithelium in vitro. Loss of Grhl2 inhibits organoid morphogenesis and the differentiation of ciliated cells and reduces the expression of both notch and ciliogenesis genes (Mcidas, Rfx2, and Myb) with distinct Grhl2 regulatory sites. The genome editing of other putative target genes reveals roles for zinc finger transcription factor Znf750 and small membrane adhesion glycoprotein in promoting ciliogenesis and barrier function as part of a network of genes coordinately regulated by Grhl2.

Authors
Gao, X; Bali, AS; Randell, SH; Hogan, BLM
MLA Citation
Gao, X, Bali, AS, Randell, SH, and Hogan, BLM. "GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells." The Journal of cell biology 211.3 (November 2, 2015): 669-682.
PMID
26527742
Source
epmc
Published In
The Journal of Cell Biology
Volume
211
Issue
3
Publish Date
2015
Start Page
669
End Page
682
DOI
10.1083/jcb.201506014

Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung.

The plasticity of differentiated cells in adult tissues undergoing repair is an area of intense research. Pulmonary alveolar type II cells produce surfactant and function as progenitors in the adult, demonstrating both self-renewal and differentiation into gas exchanging type I cells. In vivo, type I cells are thought to be terminally differentiated and their ability to give rise to alternate lineages has not been reported. Here we show that Hopx becomes restricted to type I cells during development. However, unexpectedly, lineage-labelled Hopx(+) cells both proliferate and generate type II cells during adult alveolar regrowth following partial pneumonectomy. In clonal 3D culture, single Hopx(+) type I cells generate organoids composed of type I and type II cells, a process modulated by TGFβ signalling. These findings demonstrate unanticipated plasticity of type I cells and a bidirectional lineage relationship between distinct differentiated alveolar epithelial cell types in vivo and in single-cell culture.

Authors
Jain, R; Barkauskas, CE; Takeda, N; Bowie, EJ; Aghajanian, H; Wang, Q; Padmanabhan, A; Manderfield, LJ; Gupta, M; Li, D; Li, L; Trivedi, CM; Hogan, BLM; Epstein, JA
MLA Citation
Jain, R, Barkauskas, CE, Takeda, N, Bowie, EJ, Aghajanian, H, Wang, Q, Padmanabhan, A, Manderfield, LJ, Gupta, M, Li, D, Li, L, Trivedi, CM, Hogan, BLM, and Epstein, JA. "Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung." Nature communications 6 (April 13, 2015): 6727-.
PMID
25865356
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
6727
DOI
10.1038/ncomms7727

Telomere dysfunction causes alveolar stem cell failure.

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

Authors
Alder, JK; Barkauskas, CE; Limjunyawong, N; Stanley, SE; Kembou, F; Tuder, RM; Hogan, BLM; Mitzner, W; Armanios, M
MLA Citation
Alder, JK, Barkauskas, CE, Limjunyawong, N, Stanley, SE, Kembou, F, Tuder, RM, Hogan, BLM, Mitzner, W, and Armanios, M. "Telomere dysfunction causes alveolar stem cell failure." Proceedings of the National Academy of Sciences of the United States of America 112.16 (April 3, 2015): 5099-5104.
PMID
25840590
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
16
Publish Date
2015
Start Page
5099
End Page
5104
DOI
10.1073/pnas.1504780112

Stem cells of the adult lung: Their development and role in homeostasis, regeneration, and disease [WIREs Dev Biol, 2, (2013), 131-148] doi: 10.1002/wdev.58

Authors
Wansleeben, C; Barkauskas, CE; Rock, JR; Hogan, BLM
MLA Citation
Wansleeben, C, Barkauskas, CE, Rock, JR, and Hogan, BLM. "Stem cells of the adult lung: Their development and role in homeostasis, regeneration, and disease [WIREs Dev Biol, 2, (2013), 131-148] doi: 10.1002/wdev.58." Wiley Interdisciplinary Reviews: Developmental Biology 4.3 (January 1, 2015): 311-312.
Source
scopus
Published In
Wiley Interdisciplinary Reviews: Developmental Biology
Volume
4
Issue
3
Publish Date
2015
Start Page
311
End Page
312
DOI
10.1002/wdev.184

IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells.

The pseudostratified airway epithelium of the lung contains a balanced proportion of multiciliated and secretory luminal cells that are maintained and regenerated by a population of basal stem cells. However, little is known about how these processes are modulated in vivo, and about the potential role of cytokine signaling between stem and progenitor cells and their niche. Using a clonal 3D organoid assay, we found that IL-6 stimulated, and Stat3 inhibitors reduced, the generation of ciliated vs. secretory cells from basal cells. Gain-of-function and loss-of-function studies with cultured mouse and human basal cells suggest that IL-6/Stat3 signaling promotes ciliogenesis at multiple levels, including increases in multicilin gene and forkhead box protein J1 expression and inhibition of the Notch pathway. To test the role of IL-6 in vivo genetically, we followed the regeneration of mouse tracheal epithelium after ablation of luminal cells by inhaled SO2. Stat3 is activated in basal cells and their daughters early in the repair process, correlating with an increase in Il-6 expression in platelet-derived growth factor receptor alpha(+) mesenchymal cells in the stroma. Conditional deletion in basal cells of suppressor of cytokine signaling 3, encoding a negative regulator of the Stat3 pathway, results in an increase in multiciliated cells at the expense of secretory and basal cells. By contrast, Il-6 null mice regenerate fewer ciliated cells and an increased number of secretory cells after injury. The results support a model in which IL-6, produced in the reparative niche, functions to enhance the differentiation of basal cells, and thereby acts as a "friend" to promote airway repair rather than a "foe."

Authors
Tadokoro, T; Wang, Y; Barak, LS; Bai, Y; Randell, SH; Hogan, BLM
MLA Citation
Tadokoro, T, Wang, Y, Barak, LS, Bai, Y, Randell, SH, and Hogan, BLM. "IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells." Proceedings of the National Academy of Sciences of the United States of America 111.35 (September 2014): E3641-E3649.
PMID
25136113
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
35
Publish Date
2014
Start Page
E3641
End Page
E3649
DOI
10.1073/pnas.1409781111

The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2.

Cell type-specific conditional activation of oncogenic K-Ras is a powerful tool for investigating the cell of origin of adenocarcinomas in the mouse lung. Our previous studies showed that K-Ras activation with a CC10(Scgb1a1)-CreER driver leads to adenocarcinoma in a subset of alveolar type II cells and hyperplasia in the bronchioalveolar duct region. However, no tumors develop in the bronchioles, although recombination occurs throughout this region. To explore underlying mechanisms, we simultaneously modulated either Notch signaling or Sox2 levels in the CC10+ cells along with activation of K-Ras. Inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2+, Sox9+, and CC10+ papillary adenocarcinomas throughout the bronchioles. Chromatin immunoprecipitation demonstrates Sox2 binding to NOTCH1 and NOTCH2 regulatory regions. In transgenic mouse models, overexpression of Sox2 leads to a significant reduction of Notch1 and Notch2 transcripts, while a 50% reduction in Sox2 leads to widespread papillary adenocarcinoma in the bronchioles. Taken together, our data demonstrate that the cell of origin of K-Ras-induced tumors in the lung depends on levels of Sox2 expression affecting Notch signaling. In addition, the subtype of tumors arising from type II cells is determined in part by Notch activation or suppression.

Authors
Xu, X; Huang, L; Futtner, C; Schwab, B; Rampersad, RR; Lu, Y; Sporn, TA; Hogan, BLM; Onaitis, MW
MLA Citation
Xu, X, Huang, L, Futtner, C, Schwab, B, Rampersad, RR, Lu, Y, Sporn, TA, Hogan, BLM, and Onaitis, MW. "The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2." Genes & development 28.17 (September 2014): 1929-1939.
PMID
25184679
Source
epmc
Published In
Genes & development
Volume
28
Issue
17
Publish Date
2014
Start Page
1929
End Page
1939
DOI
10.1101/gad.243717.114

Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function.

Respiratory disease is the third leading cause of death in the industrialized world. Consequently, the trachea, lungs, and cardiopulmonary vasculature have been the focus of extensive investigations. Recent studies have provided new information about the mechanisms driving lung development and differentiation. However, there is still much to learn about the ability of the adult respiratory system to undergo repair and to replace cells lost in response to injury and disease. This Review highlights the multiple stem/progenitor populations in different regions of the adult lung, the plasticity of their behavior in injury models, and molecular pathways that support homeostasis and repair.

Authors
Hogan, BLM; Barkauskas, CE; Chapman, HA; Epstein, JA; Jain, R; Hsia, CCW; Niklason, L; Calle, E; Le, A; Randell, SH; Rock, J; Snitow, M; Krummel, M; Stripp, BR; Vu, T; White, ES; Whitsett, JA; Morrisey, EE
MLA Citation
Hogan, BLM, Barkauskas, CE, Chapman, HA, Epstein, JA, Jain, R, Hsia, CCW, Niklason, L, Calle, E, Le, A, Randell, SH, Rock, J, Snitow, M, Krummel, M, Stripp, BR, Vu, T, White, ES, Whitsett, JA, and Morrisey, EE. "Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function." Cell stem cell 15.2 (August 2014): 123-138. (Review)
PMID
25105578
Source
epmc
Published In
Cell Stem Cell
Volume
15
Issue
2
Publish Date
2014
Start Page
123
End Page
138
DOI
10.1016/j.stem.2014.07.012

Age-related changes in the cellular composition and epithelial organization of the mouse trachea.

We report here senescent changes in the structure and organization of the mucociliary pseudostratified epithelium of the mouse trachea and main stem bronchi. We confirm previous reports of the gradual appearance of age-related, gland-like structures (ARGLS) in the submucosa, especially in the intercartilage regions and carina. Immunohistochemistry shows these structures contain ciliated and secretory cells and Krt5+ basal cells, but not the myoepithelial cells or ciliated ducts typical of normal submucosal glands. Data suggest they arise de novo by budding from the surface epithelium rather than by delayed growth of rudimentary or cryptic submucosal glands. In old mice the surface epithelium contains fewer cells per unit length than in young mice and the proportion of Krt5+, p63+ basal cells is reduced in both males and females. However, there appears to be no significant difference in the ability of basal stem cells isolated from individual young and old mice to form clonal tracheospheres in culture or in the ability of the epithelium to repair after damage by inhaled sulfur dioxide. Gene expression analysis by Affymetrix microarray and quantitative PCR, as well as immunohistochemistry and flow sorting studies, are consistent with low-grade chronic inflammation in the tracheas of old versus young mice and an increase in the number of immune cells. The significance of these changes for ARGL formation are not clear since several treatments that induce acute inflammation in young mice did not result in budding of the surface epithelium.

Authors
Wansleeben, C; Bowie, E; Hotten, DF; Yu, Y-RA; Hogan, BLM
MLA Citation
Wansleeben, C, Bowie, E, Hotten, DF, Yu, Y-RA, and Hogan, BLM. "Age-related changes in the cellular composition and epithelial organization of the mouse trachea." PloS one 9.3 (January 2014): e93496-.
PMID
24675804
Source
epmc
Published In
PloS one
Volume
9
Issue
3
Publish Date
2014
Start Page
e93496
DOI
10.1371/journal.pone.0093496

Loss of basal cells precedes bronchiolitis obliterans-like pathological changes in a murine model of chlorine gas inhalation

Bronchiolitis obliterans (BO) is a major cause of chronic airway dysfunction after toxic chemical inhalation. The pathophysiology of BO is not well understood, but epithelial cell injury has been closely associated with the development of fibrotic lesions in human studies and in animal models of both toxin-induced and transplantinduced BO. However, whereas almost all cases and models of BO include epithelial injury, not all instances of epithelial injury result in BO, suggesting that epithelial damage per se is not the critical event leading to the development of BO. Here, we describe a model of chlorine-induced BO in which mice develop tracheal and large airwayobliterative lesions within 10 days of exposure to high (350 parts per million [ppm]), but not low (200 ppm), concentrations of chlorine gas. Importantly, these lesions arise only under conditions and in areas in which basal cells, the resident progenitor cells for large airway epithelium, are eliminated by chlorine exposure. In areas of basal cell loss, epithelial regeneration does not occur, resulting in persistent regions of epithelial denudation. Obliterative airway lesions arise specifically from regions of epithelial denudation in a process that includes inflammatory cell infiltration by Day 2 after exposure, fibroblast infiltration and collagen deposition by Day 5, and the ingrowth of blood vessels by Day 7, ultimately leading to lethal airway obstruction by Days 9-12. We conclude that the loss of epithelial progenitor cells constitutes a critical factor leading to the developmentof obliterative airway lesions after chemical inhalation. Copyright © 2013 by the American Thoracic Society.

Authors
O'Koren, EG; Hogan, BLM; Gunn, MD
MLA Citation
O'Koren, EG, Hogan, BLM, and Gunn, MD. "Loss of basal cells precedes bronchiolitis obliterans-like pathological changes in a murine model of chlorine gas inhalation." American Journal of Respiratory Cell and Molecular Biology 49.5 (November 1, 2013): 788-797.
PMID
23742075
Source
scopus
Published In
American journal of respiratory cell and molecular biology
Volume
49
Issue
5
Publish Date
2013
Start Page
788
End Page
797
DOI
10.1165/rcmb.2012-0369OC

Type 2 alveolar cells are stem cells in adult lung.

Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.

Authors
Barkauskas, CE; Cronce, MJ; Rackley, CR; Bowie, EJ; Keene, DR; Stripp, BR; Randell, SH; Noble, PW; Hogan, BLM
MLA Citation
Barkauskas, CE, Cronce, MJ, Rackley, CR, Bowie, EJ, Keene, DR, Stripp, BR, Randell, SH, Noble, PW, and Hogan, BLM. "Type 2 alveolar cells are stem cells in adult lung." J Clin Invest 123.7 (July 2013): 3025-3036.
PMID
23921127
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
7
Publish Date
2013
Start Page
3025
End Page
3036
DOI
10.1172/JCI68782

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium.[corrected].

Most of the airways of the human lung are lined by an epithelium made up of ciliated and secretory luminal cells and undifferentiated basal progenitor cells. The integrity of this epithelium and its ability to act as a selective barrier are critical for normal lung function. In other epithelia, there is evidence that transcription factors of the evolutionarily conserved grainyheadlike (GRHL) family play key roles in coordinating multiple cellular processes required for epithelial morphogenesis, differentiation, remodeling, and repair. However, only a few target genes have been identified, and little is known about GRHL function in the adult lung. Here we focus on the role of GRHL2 in primary human bronchial epithelial cells, both as undifferentiated progenitors and as they differentiate in air-liquid interface culture into an organized mucociliary epithelium with transepithelial resistance. Using a dominant-negative protein or shRNA to inhibit GRHL2, we follow changes in epithelial phenotype and gene transcription using RNA sequencing or microarray analysis. We identify several hundreds of genes that are directly or indirectly regulated by GRHL2 in both undifferentiated cells and air-liquid interface cultures. Using ChIP sequencing to map sites of GRHL2 binding in the basal cells, we identify 7,687 potential primary targets and confirm that GRHL2 binding is strongly enriched near GRHL2-regulated genes. Taken together, the results support the hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility.

Authors
Gao, X; Vockley, CM; Pauli, F; Newberry, KM; Xue, Y; Randell, SH; Reddy, TE; Hogan, BLM
MLA Citation
Gao, X, Vockley, CM, Pauli, F, Newberry, KM, Xue, Y, Randell, SH, Reddy, TE, and Hogan, BLM. "Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium.[corrected]." Proc Natl Acad Sci U S A 110.23 (June 4, 2013): 9356-9361.
PMID
23690579
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
23
Publish Date
2013
Start Page
9356
End Page
9361
DOI
10.1073/pnas.1307589110

Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease.

The lung has vital functions in gas exchange and immune defense. To fulfill these functions the cellular composition and complex three-dimensional organization of the organ must be maintained for a lifetime. Cell turnover in the adult lung is normally low. However, in response to cellular injury by agents such as infection, toxic compounds, and irradiation there is rapid proliferation and differentiation of endogenous stem and progenitor cells to repair and regenerate the damaged tissue. In the mouse, different populations of epithelial progenitor cells have been identified in different regions of the respiratory system: basal cells in the proximal tracheobronchial region and submucosal glands, and secretory cells in the conducting airways and bronchioalveolar duct junction. The identification of the long-term stem cells in the alveolar region is still under debate, and little is known about resident stem and progenitor cells for the many mesodermal populations. Within this framework information is provided about the origin of lung progenitor cells during development, the microenvironment in which they reside, the experimental injury and repair systems used to promote their regenerative response, and some of the mechanisms regulating their behavior. WIREs Dev Biol 2013, 2:131-148. doi: 10.1002/wdev.58 For further resources related to this article, please visit the WIREs website.

Authors
Wansleeben, C; Barkauskas, CE; Rock, JR; Hogan, BLM
MLA Citation
Wansleeben, C, Barkauskas, CE, Rock, JR, and Hogan, BLM. "Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease." Wiley Interdiscip Rev Dev Biol 2.1 (January 2013): 131-148. (Review)
PMID
23799633
Source
pubmed
Published In
Wiley Interdisciplinary Reviews: Developmental Biology
Volume
2
Issue
1
Publish Date
2013
Start Page
131
End Page
148
DOI
10.1002/wdev.58

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction.

Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.

Authors
Huang, F; Zhang, H; Wu, M; Yang, H; Kudo, M; Peters, CJ; Woodruff, PG; Solberg, OD; Donne, ML; Huang, X; Sheppard, D; Fahy, JV; Wolters, PJ; Hogan, BLM; Finkbeiner, WE; Li, M; Jan, Y-N; Jan, LY; Rock, JR
MLA Citation
Huang, F, Zhang, H, Wu, M, Yang, H, Kudo, M, Peters, CJ, Woodruff, PG, Solberg, OD, Donne, ML, Huang, X, Sheppard, D, Fahy, JV, Wolters, PJ, Hogan, BLM, Finkbeiner, WE, Li, M, Jan, Y-N, Jan, LY, and Rock, JR. "Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction." Proceedings of the National Academy of Sciences of the United States of America 109.40 (October 2012): 16354-16359.
PMID
22988107
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
40
Publish Date
2012
Start Page
16354
End Page
16359
DOI
10.1073/pnas.1214596109

Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma.

Identifying the cells of origin of lung cancer may lead to new therapeutic strategies. Previous work has focused upon the putative bronchoalveolar stem cell at the bronchioalveolar duct junction as a cancer cell of origin when a codon 12 K-Ras mutant is induced via adenoviral Cre inhalation. In the present study, we use two "knock-in" Cre-estrogen receptor alleles to inducibly express K-RasG12D in CC10(+) epithelial cells and Sftpc(+) type II alveolar cells of the adult mouse lung. Analysis of these mice identifies type II cells, Clara cells in the terminal bronchioles, and putative bronchoalveolar stem cells as cells of origin for K-Ras-induced lung hyperplasia. However, only type II cells appear to progress to adenocarcinoma.

Authors
Xu, X; Rock, JR; Lu, Y; Futtner, C; Schwab, B; Guinney, J; Hogan, BLM; Onaitis, MW
MLA Citation
Xu, X, Rock, JR, Lu, Y, Futtner, C, Schwab, B, Guinney, J, Hogan, BLM, and Onaitis, MW. "Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma." Proc Natl Acad Sci U S A 109.13 (March 27, 2012): 4910-4915.
PMID
22411819
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
13
Publish Date
2012
Start Page
4910
End Page
4915
DOI
10.1073/pnas.1112499109

Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.

There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreER(T2) knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.

Authors
Rock, JR; Barkauskas, CE; Cronce, MJ; Xue, Y; Harris, JR; Liang, J; Noble, PW; Hogan, BLM
MLA Citation
Rock, JR, Barkauskas, CE, Cronce, MJ, Xue, Y, Harris, JR, Liang, J, Noble, PW, and Hogan, BLM. "Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition." Proc Natl Acad Sci U S A 108.52 (December 27, 2011): E1475-E1483.
PMID
22123957
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
52
Publish Date
2011
Start Page
E1475
End Page
E1483
DOI
10.1073/pnas.1117988108

Lung stem cells: looking beyond the hype

MLA Citation
"Lung stem cells: looking beyond the hype." Nature Medicine 17.7 (July 7, 2011): 788-789.
Source
crossref
Published In
Nature Medicine
Volume
17
Issue
7
Publish Date
2011
Start Page
788
End Page
789
DOI
10.1038/nm0711-788

Notch-dependent differentiation of adult airway basal stem cells

The epithelium lining the airways of the adult human lung is composed of ciliated and secretory cells together with undifferentiated basal cells (BCs). The composition and organization of this epithelium is severely disrupted in many respiratory diseases. However, little is known about the mechanisms controlling airway homeostasis and repair after epithelial damage. Here, we exploit the mouse tracheobronchial epithelium, in which BCs function as resident stem cells, as a genetically tractable model of human small airways. Using a reporter allele we show that the low level of Notch signaling at steady state is greatly enhanced during repair and the generation of luminal progenitors. Loss-of-function experiments show that Notch signaling is required for the differentiation, but not self-renewal, of BCs. Moreover, sustained Notch activation in BCs promotes their luminal differentiation, primarily toward secretory lineages. We also provide evidence that this function of Notch signaling is conserved in BCs from human airways. © 2011 Elsevier Inc.

Authors
Rock, JR; Gao, X; Xue, Y; Randell, SH; Kong, Y-Y; Hogan, BLM
MLA Citation
Rock, JR, Gao, X, Xue, Y, Randell, SH, Kong, Y-Y, and Hogan, BLM. "Notch-dependent differentiation of adult airway basal stem cells." Cell Stem Cell 8.6 (2011): 639-648.
PMID
21624809
Source
scival
Published In
Cell Stem Cell
Volume
8
Issue
6
Publish Date
2011
Start Page
639
End Page
648
DOI
10.1016/j.stem.2011.04.003

Cell plasticity in lung injury and repair: Report from an NHLBI Workshop, April 19-20, 2010

In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular,maybe an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation andan active contributor todisease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.

Authors
Borok, Z; Whitsett, JA; Bitterman, PB; Thannickal, VJ; Kotton, DN; Reynolds, SD; Krasnow, MA; Bianchi, DW; Morrisey, EE; Hogan, BL; Kurie, JM; Walker, DC; Radisky, DC; Nishimura, SL; Violette, SM; Noble, PW; Shapiro, SD; Blaisdell, CJ; Chapman, HA; Kiley, J; Gail, D; Hoshizaki, D
MLA Citation
Borok, Z, Whitsett, JA, Bitterman, PB, Thannickal, VJ, Kotton, DN, Reynolds, SD, Krasnow, MA, Bianchi, DW, Morrisey, EE, Hogan, BL, Kurie, JM, Walker, DC, Radisky, DC, Nishimura, SL, Violette, SM, Noble, PW, Shapiro, SD, Blaisdell, CJ, Chapman, HA, Kiley, J, Gail, D, and Hoshizaki, D. "Cell plasticity in lung injury and repair: Report from an NHLBI Workshop, April 19-20, 2010." Proceedings of the American Thoracic Society 8.3 (2011): 215-222.
PMID
21653526
Source
scival
Published In
Proceedings of the American Thoracic Society
Volume
8
Issue
3
Publish Date
2011
Start Page
215
End Page
222
DOI
10.1513/pats.201012-067CB

Role of e-cadherin in the pathogenesis of gastroesophageal reflux disease

Objectives: An early event in the pathogenesis of gastroesophageal reflux disease (GERD) is an acid-induced increase in junctional (paracellular) permeability in esophageal epithelium (EE). The molecular events that account for this change are unknown. E-cadherin is a junctional protein important in barrier function in EE. Therefore, defects in barrier function in EE were sought in GERD as well as whether their presence correlated with abnormalities in e-cadherin. Methods: Endoscopic biopsies of EE from GERD (n20; male 10; female 10; mean age 5010 years) and subjects with a healthy esophagus (controls; n23; male 11; female 12; mean age 5111 years) were evaluated in mini-Ussing chambers and by western blot and immunochemistry; and serum analyzed by enzyme-linked immunosorbent assay (ELISA). A role for e-cadherin was also assessed using a unique conditional knockout of e-cadherin in adult mouse esophagus. Results: EE from GERD patients had lower electrical resistance and higher fluorescein flux than EE from controls; and the findings in GERD associated with cleavage of e-cadherin. Cleavage of e-cadherin in GERD was documented in EE by the presence of a 35-kDa, C-terminal fragment of the molecule on western blot and by an increase in soluble N-terminal fragments of the molecule in serum. Activation of the membrane metalloproteinase, A Disintegrin And Metalloproteinase (ADAM-10), was identified as a likely cause for cleavage of e-cadherin by western blot and immunostaining and a role for e-cadherin in the increased junctional permeability in EE from GERD supported by showing increased permeability after deletion of e-cadherin in mouse EE. Conclusions: The EE in GERD has increased junctional permeability and this is in association with proteolytic cleavage of e-cadherin. As loss of e-cadherin can, alone, account for the increase in junctional permeability, cleavage of e-cadherin likely represents a critical molecular event in the pathogenesis of GERD, and identification of cleaved fragments may, if confirmed in larger studies, be valuable as a biomarker of GERD. © 2011 by the American College of Gastroenterology.

Authors
Jovov, B; Que, J; Tobey, NA; Djukic, Z; Hogan, BLM; Orlando, RC
MLA Citation
Jovov, B, Que, J, Tobey, NA, Djukic, Z, Hogan, BLM, and Orlando, RC. "Role of e-cadherin in the pathogenesis of gastroesophageal reflux disease." American Journal of Gastroenterology 106.6 (2011): 1039-1047.
PMID
21448147
Source
scival
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
106
Issue
6
Publish Date
2011
Start Page
1039
End Page
1047
DOI
10.1038/ajg.2011.102

Epithelial progenitor cells in lung development, maintenance, repair, and disease

The vertebrate lung is elegantly patterned to carry out gas exchange and host defense. Similar to other organ systems, endogenous stem and progenitor cells fuel the organogenesis of the lung and maintain homeostasis in the face of normal wear and tear. In the context of acute injury, these progenitor populations are capable of effecting efficient repair. However, chronic injury, inflammation, and immune rejection frequently result in pathological airway remodeling and serious impairment of lung function. Here, we review the development, maintenance, and repair of the vertebrate respiratory system with an emphasis on the roles of epithelial stem and progenitor cells. We discuss what is currently known about their identities, lineage relationships, and the mechanisms that regulate their differentiation along various lineages. A deeper understanding of these progenitor populations will undoubtedly accelerate the discovery of improved cellular, genetic, molecular, and bioengineered therapies for lung disease. © 2011 by Annual Reviews. All rights reserved.

Authors
Rock, JR; Hogan, BLM
MLA Citation
Rock, JR, and Hogan, BLM. "Epithelial progenitor cells in lung development, maintenance, repair, and disease." Annual Review of Cell and Developmental Biology 27 (2011): 493-512.
PMID
21639799
Source
scival
Published In
Annual Review of Cell and Developmental Biology
Volume
27
Publish Date
2011
Start Page
493
End Page
512
DOI
10.1146/annurev-cellbio-100109-104040

BMP signaling in the development of the mouse esophagus and forestomach.

The stratification and differentiation of the epidermis are known to involve the precise control of multiple signaling pathways. By contrast, little is known about the development of the mouse esophagus and forestomach, which are composed of a stratified squamous epithelium. Based on prior work in the skin, we hypothesized that bone morphogenetic protein (BMP) signaling is a central player. To test this hypothesis, we first used a BMP reporter mouse line harboring a BRE-lacZ allele, along with in situ hybridization to localize transcripts for BMP signaling components, including various antagonists. We then exploited a Shh-Cre allele that drives recombination in the embryonic foregut epithelium to generate gain- or loss-of-function models for the Bmpr1a (Alk3) receptor. In gain-of-function (Shh-Cre;Rosa26(CAG-loxpstoploxp-caBmprIa)) embryos, high levels of ectopic BMP signaling stall the transition from simple columnar to multilayered undifferentiated epithelium in the esophagus and forestomach. In loss-of-function experiments, conditional deletion of the BMP receptor in Shh-Cre;Bmpr1a(flox/flox) embryos allows the formation of a multilayered squamous epithelium but this fails to differentiate, as shown by the absence of expression of the suprabasal markers loricrin and involucrin. Together, these findings suggest multiple roles for BMP signaling in the developing esophagus and forestomach.

Authors
Rodriguez, P; Da Silva, S; Oxburgh, L; Wang, F; Hogan, BLM; Que, J
MLA Citation
Rodriguez, P, Da Silva, S, Oxburgh, L, Wang, F, Hogan, BLM, and Que, J. "BMP signaling in the development of the mouse esophagus and forestomach." Development 137.24 (December 2010): 4171-4176.
Website
http://hdl.handle.net/10161/4178
PMID
21068065
Source
pubmed
Published In
Development (Cambridge)
Volume
137
Issue
24
Publish Date
2010
Start Page
4171
End Page
4176
DOI
10.1242/dev.056077

Evidence that SOX2 overexpression is oncogenic in the lung.

BACKGROUND: SOX2 (Sry-box 2) is required to maintain a variety of stem cells, is overexpressed in some solid tumors, and is expressed in epithelial cells of the lung. METHODOLOGY/PRINCIPAL FINDINGS: We show that SOX2 is overexpressed in human squamous cell lung tumors and some adenocarcinomas. We have generated mouse models in which Sox2 is upregulated in epithelial cells of the lung during development and in the adult. In both cases, overexpression leads to extensive hyperplasia. In the terminal bronchioles, a trachea-like pseudostratified epithelium develops with p63-positive cells underlying columnar cells. Over 12-34 weeks, about half of the mice expressing the highest levels of Sox2 develop carcinoma. These tumors resemble adenocarcinoma but express the squamous marker, Trp63 (p63). CONCLUSIONS: These findings demonstrate that Sox2 overexpression both induces a proximal phenotype in the distal airways/alveoli and leads to cancer.

Authors
Lu, Y; Futtner, C; Rock, JR; Xu, X; Whitworth, W; Hogan, BLM; Onaitis, MW
MLA Citation
Lu, Y, Futtner, C, Rock, JR, Xu, X, Whitworth, W, Hogan, BLM, and Onaitis, MW. "Evidence that SOX2 overexpression is oncogenic in the lung. (Published online)" PLoS One 5.6 (June 10, 2010): e11022-.
Website
http://hdl.handle.net/10161/4546
PMID
20548776
Source
pubmed
Published In
PloS one
Volume
5
Issue
6
Publish Date
2010
Start Page
e11022
DOI
10.1371/journal.pone.0011022

Branching takes nerve

Innervation is required to maintain epithelial progenitor cells that support salivary gland growth and development.

Authors
Rock, JR; Hogan, BLM
MLA Citation
Rock, JR, and Hogan, BLM. "Branching takes nerve." Science 329.5999 (2010): 1610-1611.
PMID
20929836
Source
scival
Published In
Science
Volume
329
Issue
5999
Publish Date
2010
Start Page
1610
End Page
1611
DOI
10.1126/science.1196016

Airway basal stem cells: A perspective on their roles in epithelial homeostasis and remodeling

The small airways of the human lung undergo pathological changes in pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), asthma, bronchiolitis obliterans and cystic fibrosis. These clinical problems impose huge personal and societal healthcare burdens. The changes, termed 'pathological airway remodeling', affect the epithelium, the underlying mesenchyme and the reciprocal trophic interactions that occur between these tissues. Most of the normal human airway is lined by a pseudostratified epithelium of ciliated cells, secretory cells and 6-30% basal cells, the proportion of which varies along the proximal-distal axis. Epithelial abnormalities range from hypoplasia (failure to differentiate) to basal- and goblet-cell hyperplasia, squamous- and goblet-cell metaplasia, dysplasia and malignant transformation. Mesenchymal alterations include thickening of the basal lamina, smooth muscle hyperplasia, fibrosis and inflammatory cell accumulation. Paradoxically, given the prevalence and importance of airway remodeling in lung disease, its etiology is poorly understood. This is due, in part, to a lack of basic knowledge of the mechanisms that regulate the differentiation, maintenance and repair of the airway epithelium. Specifically, little is known about the proliferation and differentiation of basal cells, a multipotent stem cell population of the pseudostratified airway epithelium. This Perspective summarizes what we know, and what we need to know, about airway basal cells to evaluate their contributions to normal and abnormal airway remodeling. We contend that exploiting well-described model systems using both human airway epithelial cells and the pseudostratified epithelium of the genetically tractable mouse trachea will enable crucial discoveries regarding the pathogenesis of airway disease. © 2010. Published by The Company of Biologists Ltd.

Authors
Rock, JR; Randell, SH; Hogan, BLM
MLA Citation
Rock, JR, Randell, SH, and Hogan, BLM. "Airway basal stem cells: A perspective on their roles in epithelial homeostasis and remodeling." DMM Disease Models and Mechanisms 3.9-10 (2010): 545-556.
Website
http://hdl.handle.net/10161/4184
PMID
20699479
Source
scival
Published In
Disease models & mechanisms
Volume
3
Issue
9-10
Publish Date
2010
Start Page
545
End Page
556
DOI
10.1242/dmm.006031

Preparing for the First Breath: Genetic and Cellular Mechanisms in Lung Development

The mammalian respiratory system-the trachea and the lungs-arises from the anterior foregut through a sequence of morphogenetic events involving reciprocal endodermal-mesodermal interactions. The lung itself consists of two highly branched, tree-like systems-the airways and the vasculature-that develop in a coordinated way from the primary bud stage to the generation of millions of alveolar gas exchange units. We are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes such as branching morphogenesis, vascular development, and the differentiation of multipotent progenitor populations. Nevertheless, many gaps remain in our knowledge, the filling of which is essential for understanding respiratory disorders, congenital defects in human neonates, and how the disruption of morphogenetic programs early in lung development can lead to deficiencies that persist throughout life. © 2010 Elsevier Inc. All rights reserved.

Authors
Morrisey, EE; Hogan, BLM
MLA Citation
Morrisey, EE, and Hogan, BLM. "Preparing for the First Breath: Genetic and Cellular Mechanisms in Lung Development." Developmental Cell 18.1 (2010): 8-23.
PMID
20152174
Source
scival
Published In
Developmental Cell
Volume
18
Issue
1
Publish Date
2010
Start Page
8
End Page
23
DOI
10.1016/j.devcel.2009.12.010

Basal cells as stem cells of the mouse trachea and human airway epithelium.

The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.

Authors
Rock, JR; Onaitis, MW; Rawlins, EL; Lu, Y; Clark, CP; Xue, Y; Randell, SH; Hogan, BLM
MLA Citation
Rock, JR, Onaitis, MW, Rawlins, EL, Lu, Y, Clark, CP, Xue, Y, Randell, SH, and Hogan, BLM. "Basal cells as stem cells of the mouse trachea and human airway epithelium." Proc Natl Acad Sci U S A 106.31 (August 4, 2009): 12771-12775.
PMID
19625615
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
31
Publish Date
2009
Start Page
12771
End Page
12775
DOI
10.1073/pnas.0906850106

The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium.

To directly test the contribution of Scgb1a1(+) Clara cells to postnatal growth, homeostasis, and repair of lung epithelium, we generated a Scgb1a1-CreER "knockin" mouse for lineage-tracing these cells. Under all conditions tested, the majority of Clara cells in the bronchioles both self-renews and generates ciliated cells. In the trachea, Clara cells give rise to ciliated cells but do not self-renew extensively. Nevertheless, they can contribute to tracheal repair. In the postnatal mouse lung, it has been proposed that bronchioalveolar stem cells (BASCs) which coexpress Scgb1a1 (Secretoglobin1a1) and SftpC (Surfactant Protein C), contribute descendants to both bronchioles and alveoli. The putative BASCs were lineage labeled in our studies. However, we find no evidence for the function of a special BASC population during postnatal growth, adult homeostasis, or repair. Rather, our results support a model in which the trachea, bronchioles, and alveoli are maintained by distinct populations of epithelial progenitor cells.

Authors
Rawlins, EL; Okubo, T; Xue, Y; Brass, DM; Auten, RL; Hasegawa, H; Wang, F; Hogan, BLM
MLA Citation
Rawlins, EL, Okubo, T, Xue, Y, Brass, DM, Auten, RL, Hasegawa, H, Wang, F, and Hogan, BLM. "The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium." Cell Stem Cell 4.6 (June 5, 2009): 525-534.
PMID
19497281
Source
pubmed
Published In
Cell Stem Cell
Volume
4
Issue
6
Publish Date
2009
Start Page
525
End Page
534
DOI
10.1016/j.stem.2009.04.002

Cell lineage mapping of taste bud cells and keratinocytes in the mouse tongue and soft palate.

The epithelium of the mouse tongue and soft palate consists of at least three distinct epithelial cell populations: basal cells, keratinized cells organized into filiform and fungiform papillae, and taste receptor cells present in tight clusters known as taste buds in the fungiform and circumvallate papillae and soft palate. All three cell types develop from the simple epithelium of the embryonic tongue and palate, and are continually replaced in the adult by cell turnover. Previous studies using pulse-chase tritiated thymidine labeling in the adult mouse provided evidence for a high rate of cell turnover in the keratinocytes (5-7 days) and taste buds (10 days). However, little is known about the localization and phenotype of the long-term stem or progenitor cells that give rise to the mature taste bud cells and surrounding keratinocytes in these gustatory tissues. Here, we make use of a tamoxifen-inducible K14-CreER transgene and the ROSA26 LacZ reporter allele to lineage trace the mature keratinocytes and taste bud cells of the early postnatal and adult mouse tongue and soft palate. Our results support the hypothesis that both the pore keratinocytes and receptor cells of the taste bud are derived from a common K14(+)K5(+)Trp63(+)Sox2(+) population of bipotential progenitor cells located outside the taste bud. The results are also compatible with models in which the keratinocytes of the filiform and fungiform papillae are derived from basal progenitor cells localized at the base of these structures.

Authors
Okubo, T; Clark, C; Hogan, BLM
MLA Citation
Okubo, T, Clark, C, and Hogan, BLM. "Cell lineage mapping of taste bud cells and keratinocytes in the mouse tongue and soft palate." Stem Cells 27.2 (February 2009): 442-450.
PMID
19038788
Source
pubmed
Published In
Stem Cells
Volume
27
Issue
2
Publish Date
2009
Start Page
442
End Page
450
DOI
10.1634/stemcells.2008-0611

Essentials of Stem Cell Biology

First developed as an accessible abridgement of the successful Handbook of Stem Cells, Essentials of Stem Cell Biology serves the needs of the evolving population of scientists, researchers, practitioners and students that are embracing the latest advances in stem cells. Representing the combined effort of seven editors and more than 200 scholars and scientists whose pioneering work has defined our understanding of stem cells, this book combines the prerequisites for a general understanding of adult and embryonic stem cells with a presentation by the world's experts of the latest research information about specific organ systems. From basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and ethics, and patient perspectives, no topic in the field of stem cells is left uncovered. * Contributions by Nobel Laureates and leading international investigators * Includes two entirely new chapters devoted exclusively to iPS written by the scientists who made the breakthroug * Edited by a world-renowned author and researcher to present a complete story of stem cells in research, in application, and as the subject of political debate. First developed as an accessible abridgement of the successful Handbook of Stem Cells, Essentials of Stem Cell Biology serves the needs of the evolving population of scientists, researchers, practitioners and students that are embracing the latest advances in stem cells. Representing the combined effort of seven editors and more than 200 scholars and scientists whose pioneering work has defined our understanding of stem cells, this book combines the prerequisites for a general understanding of adult and embryonic stem cells with a presentation by the world's experts of the latest research information about specific organ systems. From basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and ethics, and patient perspectives, no topic in the field of stem cells is left uncovered. * Contributions by Nobel Laureates and leading international investigators * Includes two entirely new chapters devoted exclusively to iPS written by the scientists who made the breakthroug * Edited by a world-renowned author and researcher to present a complete story of stem cells in research, in application, and as the subject of political debate. © 2009 Elsevier Inc. All rights reserved.

Authors
Lanza, R; Gearhart, J; Hogan, B; Melton, D; Pedersen, R; Thomas, ED; Thomson, J; Wilmut, SI
MLA Citation
Lanza, R, Gearhart, J, Hogan, B, Melton, D, Pedersen, R, Thomas, ED, Thomson, J, and Wilmut, SI. Essentials of Stem Cell Biology. January 1, 2009.
Source
scopus
Publish Date
2009
DOI
10.1016/C2009-0-00078-6

The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells

The conducting airways (bronchi and bronchioles) and peripheral gas exchange (alveolar) regions of the mammalian lung are generated by a process of branching morphogenesis. Evidence suggests that during embryonic development, the undifferentiated epithelial progenitors are located at the distal tips of the branching epithelium. To test this hypothesis, we used an Id2-CreERT2 knock-in mouse strain to lineage trace the distal epithelial tip cells during either the pseudoglandular or canalicular phases of development. During the pseudoglandular stage, the tip cells both self-renew and contribute descendents to all epithelial cell lineages, including neuroendocrine cells. In addition, individual Id2+ tip cells can self-renew and contribute descendents to both the bronchiolar and alveolar compartments. By contrast, during the later canalicular stage, the distal epithelial tip cells only contribute descendents to the alveoli. Taken together, this evidence supports a model in which the distal tip of the developing lung contains a multipotent epithelial population, the fate of which changes during development.

Authors
Rawlins, EL; Clark, CP; Xue, Y; Hogan, BLM
MLA Citation
Rawlins, EL, Clark, CP, Xue, Y, and Hogan, BLM. "The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells." Development 136.22 (2009): 3741-3745.
PMID
19855016
Source
scival
Published In
Development (Cambridge)
Volume
136
Issue
22
Publish Date
2009
Start Page
3741
End Page
3745
DOI
10.1242/dev.037317

Multiple roles for Sox2 in the developing and adult mouse trachea

The esophagus, trachea and lung develop from the embryonic foregut, yet acquire and maintain distinct tissue phenotypes. Previously, we demonstrated that the transcription factor Sox2 is necessary for foregut morphogenesis and esophagus development. We show that Sox2 is also required for the normal development of the trachea and lung. In both the embryo and adult, Sox2 is exclusively expressed in the epithelium of the trachea and airways. We use an Nkx2.5-Cre transgene and a Sox2 floxed allele to conditionally delete Sox2 in the ventral epithelial domain of the early anterior foregut, which gives rise to the future trachea and lung buds. All conditional mutants die of respiratory distress at birth, probably due to abnormal differentiation of the laryngeal and tracheal cartilage as a result of defective epithelial-mesenchymal interaction. About 60% of the mutants have a short trachea, suggesting that the primary budding site of the lung shifts anteriorly. In the tracheal epithelium of all conditional mutants there are significantly more mucus-producing cells compared with wild type, and fewer basal stem cells, ciliated and Clara cells. Differentiation of the epithelium lining the conducting airways in the lung is abnormal, suggesting that Sox2 also plays a role in the differentiation of embryonic airway progenitors into specific lineages. Conditional deletion of Sox2 was then used to test its role in adult epithelium maintenance. We found that epithelial cells, including basal stem cells, lacking Sox2 show a reduced capacity to proliferate in culture and to repair after injury in vivo. Taken together, these results define multiple roles for Sox2 in the developing and adult trachea.

Authors
Que, J; Luo, X; Schwartz, RJ; Hogan, BLM
MLA Citation
Que, J, Luo, X, Schwartz, RJ, and Hogan, BLM. "Multiple roles for Sox2 in the developing and adult mouse trachea." Development 136.11 (2009): 1899-1907.
PMID
19403656
Source
scival
Published In
Development (Cambridge)
Volume
136
Issue
11
Publish Date
2009
Start Page
1899
End Page
1907
DOI
10.1242/dev.034629

Culture of endodermal stem/progenitor cells of the mouse tongue

The tongue represents a very accessible source of tissue-specific epithelial stem cells of endodermal origin. However, little is known about the properties of these cells and the mechanisms regulating their proliferation and differentiation. Foxa2, an endodermal marker, is expressed throughout the tongue epithelium during embryonic development but becomes confined to a minority of basal cells and some taste bud sensory cells in the adult tongue. Using a previously described line of transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed under the control of a human keratin 5 promoter region (Krt5-eGFP), we have isolated a subpopulation of cells in the basal epithelial layer of the mouse tongue with a high efficiency of generating holoclones of undifferentiated cells in culture with a feeder layer. Krt5-GFPhi cells can both self renew and give rise to differentiated stratified keratinized epithelial cells when cultured on an air-liquid interface. © 2008 The Society for In Vitro Biology.

Authors
Luo, X; Okubo, T; Randell, S; Hogan, BLM
MLA Citation
Luo, X, Okubo, T, Randell, S, and Hogan, BLM. "Culture of endodermal stem/progenitor cells of the mouse tongue." In Vitro Cellular and Developmental Biology - Animal 45.1-2 (2009): 44-54.
PMID
18830772
Source
scival
Published In
In Vitro Cellular & Developmental Biology - Animal
Volume
45
Issue
1-2
Publish Date
2009
Start Page
44
End Page
54
DOI
10.1007/s11626-008-9149-2

Essentials of Stem Cell Biology

First developed as an accessible abridgement of the successful Handbook of Stem Cells, Essentials of Stem Cell Biology serves the needs of the evolving population of scientists, researchers, practitioners and students that are embracing the latest advances in stem cells. Representing the combined effort of seven editors and more than 200 scholars and scientists whose pioneering work has defined our understanding of stem cells, this book combines the prerequisites for a general understanding of adult and embryonic stem cells with a presentation by the world's experts of the latest research information about specific organ systems. From basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and ethics, and patient perspectives, no topic in the field of stem cells is left uncovered. * Contributions by Nobel Laureates and leading international investigators * Includes two entirely new chapters devoted exclusively to iPS written by the scientists who made the breakthroug * Edited by a world-renowned author and researcher to present a complete story of stem cells in research, in application, and as the subject of political debate. First developed as an accessible abridgement of the successful Handbook of Stem Cells, Essentials of Stem Cell Biology serves the needs of the evolving population of scientists, researchers, practitioners and students that are embracing the latest advances in stem cells. Representing the combined effort of seven editors and more than 200 scholars and scientists whose pioneering work has defined our understanding of stem cells, this book combines the prerequisites for a general understanding of adult and embryonic stem cells with a presentation by the world's experts of the latest research information about specific organ systems. From basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and ethics, and patient perspectives, no topic in the field of stem cells is left uncovered. * Contributions by Nobel Laureates and leading international investigators * Includes two entirely new chapters devoted exclusively to iPS written by the scientists who made the breakthroug * Edited by a world-renowned author and researcher to present a complete story of stem cells in research, in application, and as the subject of political debate. © 2009 Elsevier Inc. All rights reserved.

Authors
Lanza, R; Gearhart, J; Hogan, B; Melton, D; Pedersen, R; Thomas, ED; Thomson, J; Wilmut, SI
MLA Citation
Lanza, R, Gearhart, J, Hogan, B, Melton, D, Pedersen, R, Thomas, ED, Thomson, J, and Wilmut, SI. "Essentials of Stem Cell Biology." Essentials of Stem Cell Biology (2009).
Source
scival
Published In
Essentials of Stem Cell Biology
Publish Date
2009

Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development.

During mouse development, the sophisticated vascular network of the lung is established from embryonic day (E) approximately 10.5 and continues to develop postnatally. This network is composed of endothelial cells enclosed by vascular smooth muscle, pericytes, and other mesenchymal cells. Recent in vivo lineage labeling studies in the developing heart and intestine suggest that some of the vascular smooth muscle cells arise from the surface mesothelium. In the developing lung, the Wilm's tumor 1 gene (Wt1) is expressed only in the mesothelial cells. Therefore, we lineage-labeled the mesothelium in vivo by using a Wt1-Cre transgene in combination with either Rosa26R(lacZ), Rosa26R(CAG-hPLAP), or Rosa26R(EYFP) reporter alleles. In all three cases, cells derived from lineage-labeled mesothelium are found inside the lung and as smooth muscle actin (SMA) and PDGF receptor-beta positive cells in the walls of pulmonary blood vessels. To corroborate this finding, we used 5-(and-6)-carboxy-2',7'-dichlorofluorescein diacetate, succinimidyl ester "mixed isomers" (CCFSE) dye to label mesothelial cells on the surface of the embryonic lung. Over the course of 72-h culture, dye-labeled cells also appear within the lung mesenchyme. Together, our data provide evidence that mesothelial cells serve as a source of vascular smooth muscle cells in the developing lung and suggest that a conserved mechanism applies to the development of blood vessels in all coelomic organs.

Authors
Que, J; Wilm, B; Hasegawa, H; Wang, F; Bader, D; Hogan, BLM
MLA Citation
Que, J, Wilm, B, Hasegawa, H, Wang, F, Bader, D, and Hogan, BLM. "Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development." Proc Natl Acad Sci U S A 105.43 (October 28, 2008): 16626-16630.
PMID
18922767
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
105
Issue
43
Publish Date
2008
Start Page
16626
End Page
16630
DOI
10.1073/pnas.0808649105

Basal cells in lung cancer

Authors
Erhunmwunsee, L; Lu, Y; Luo, X; Jr, HDH; Hogan, BLM; Onaitis, MW
MLA Citation
Erhunmwunsee, L, Lu, Y, Luo, X, Jr, HDH, Hogan, BLM, and Onaitis, MW. "Basal cells in lung cancer." September 2008.
Source
wos-lite
Published In
Journal of The American College of Surgeons
Volume
207
Issue
3
Publish Date
2008
Start Page
S30
End Page
S30
DOI
10.1016/j.jamcollsurg.2008.06.053

Ciliated epithelial cell lifespan in the mouse trachea and lung

The steady-state turnover of epithelial cells in the lung and trachea is highly relevant to investigators who are studying endogenous stem cells, manipulating gene expression in vivo, or using viral vectors for gene therapy. However, the average lifetime of different airway epithelial cell types has not previously been assessed using currently available genetic techniques. Here, we use Cre/loxP genetic technology to indelibly label a random fraction of ciliated cells throughout the airways of a cohort of mice and follow them in vivo for up to 18 mo. We demonstrate that ciliated airway epithelial cells are a terminally differentiated population. Moreover, their average half-life of 6 mo in the trachea and 17 mo in the lung is much longer than previously available estimates, with significant numbers of labeled cells still present after 18 mo. Copyright © 2008 the American Physiological Society.

Authors
Rawlins, EL; Hogan, BLM
MLA Citation
Rawlins, EL, and Hogan, BLM. "Ciliated epithelial cell lifespan in the mouse trachea and lung." American Journal of Physiology - Lung Cellular and Molecular Physiology 295.1 (2008): L231-L234.
PMID
18487354
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
295
Issue
1
Publish Date
2008
Start Page
L231
End Page
L234
DOI
10.1152/ajplung.90209.2008

Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-β), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.

Authors
Chang, W; Lin, Z; Kulessa, H; Hebert, J; Hogan, BLM; Wu, DK
MLA Citation
Chang, W, Lin, Z, Kulessa, H, Hebert, J, Hogan, BLM, and Wu, DK. "Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements." PLoS Genetics 4.4 (2008).
PMID
18404215
Source
scival
Published In
PLoS genetics
Volume
4
Issue
4
Publish Date
2008
DOI
10.1371/journal.pgen.1000050

Endothelial Bmp4 Is Induced During Arterial Remodeling: Effects on Smooth Muscle Cell Migration and Proliferation

Background: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of proteins that have multiple functional roles in mammalian development. A role for BMP4 in adult vascular remodeling has recently been suggested. We evaluated the expression of Bmp4 during neointimal lesion development in vivo. Materials and methods: Heterozygous Bmp4lacZ/+ mice were used to evaluate in vivo Bmp4 expression after carotid ligation. β-galactosidase (β-gal) activity was evaluated in histological sections 1 to 14 d after carotid ligation and this was compared with control carotid arteries. The effects of recombinant human (rh) BMP4 on smooth muscle cell (SMC) migration and proliferation were evaluated using a rat aortic SMC line. We next assessed the effects of BMP4 signaling by over-expressing a constitutively active BMP receptor (BMPR-IA/Alk-3) using adenovirus-mediated gene transfer. SMC proliferation, migration, and apoptosis were evaluated in adenovirus transfected cells. Results: Ligated carotid arteries expressed endothelium-specific β-gal staining after 1 d. Staining intensity increased at both 3 d and 1 wk after ligation and remained stable at 2 weeks while no β-gal staining was observed in control vessels. Endothelial-specific expression of β-galactosidase was confirmed through positive staining for PECAM-1. When human recombinant BMP4 was added to cultured SMCs, it inhibited migration but did not affect cultured SMC proliferation. SMCs infected with adenovirus encoding for the active BMP receptor Alk-3 demonstrated dose-dependent receptor expression. Alk-3 over-expressing cells showed a dose-dependent decrease in proliferation and migration but no effect on apoptosis. Conclusions: These results demonstrate that endothelial Bmp4 expression is upregulated after carotid ligation in vivo, and furthermore, that activating the BMP signaling cascade results in decreased SMC proliferation and migration. This suggests that BMPs may counterbalance the effect of mitogen up-regulation observed during the development of neointimal hyperplasia. © 2008 Elsevier Inc. All rights reserved.

Authors
Corriere, MA; Rogers, CM; Eliason, JL; Faulk, J; Kume, T; Hogan, BLM; Guzman, RJ
MLA Citation
Corriere, MA, Rogers, CM, Eliason, JL, Faulk, J, Kume, T, Hogan, BLM, and Guzman, RJ. "Endothelial Bmp4 Is Induced During Arterial Remodeling: Effects on Smooth Muscle Cell Migration and Proliferation." Journal of Surgical Research 145.1 (2008): 142-149.
PMID
17706674
Source
scival
Published In
Journal of Surgical Research
Volume
145
Issue
1
Publish Date
2008
Start Page
142
End Page
149
DOI
10.1016/j.jss.2007.03.077

Epithelial progenitor cells of the embryonic lung and the role of microRNAs in their proliferation

The entire epithelium of the lung is generated from a small pool of undifferentiated progenitor cells. At least during the early stages of development these reside in the distal tips of the embryonic lung. They respond to multiple signals from the surrounding mesenchyme and play a critical role as morphogenetic organizing centers. In addition, they proliferate rapidly and give rise to daughter cells that differentiate into all the specialized epithelial cells types of the newborn lung. Despite the importance of the progenitor cells, we still know relatively little about the mechanisms controlling their proliferation, morphogenesis, and developmental fate. Here, we discuss new data on the potential role of microRNAs in co-coordinately regulating multiple signaling pathways in embryonic progenitor cells. In particular, our recent transgenic experiments suggest that microRNAs encoded by the miR-17-92 cluster positively promote proliferation of epithelial progenitor cells and inhibit their differentiation. We speculate on how this information might be exploited therapeutically in the long term.

Authors
Lu, Y; Okubo, T; Rawlins, E; Hogan, BLM
MLA Citation
Lu, Y, Okubo, T, Rawlins, E, and Hogan, BLM. "Epithelial progenitor cells of the embryonic lung and the role of microRNAs in their proliferation." Proceedings of the American Thoracic Society 5.3 (2008): 300-304.
PMID
18403323
Source
scival
Published In
Proceedings of the American Thoracic Society
Volume
5
Issue
3
Publish Date
2008
Start Page
300
End Page
304
DOI
10.1513/pats.200710-162DR

Epithelial stem/progenitor cells in lung postnatal growth, maintenance, and repair.

The adult lung consists of a trachea leading into a system of branched airways ending in millions of alveolar sacs. It contains many different epithelial cell types arranged in precise patterns along the proximodistal axis. Each region of the lung has the capacity to repair through the proliferation of different epithelial cell types. However, the precise identity of the cells mediating repair is not fully resolved. To address this problem, we are using genetic lineage-labeling techniques in the mouse. The tools we have made will also be useful for understanding how progenitor cell behavior is regulated under normal and pathological conditions.

Authors
Rawlins, EL; Okubo, T; Que, J; Xue, Y; Clark, C; Luo, X; Hogan, BLM
MLA Citation
Rawlins, EL, Okubo, T, Que, J, Xue, Y, Clark, C, Luo, X, and Hogan, BLM. "Epithelial stem/progenitor cells in lung postnatal growth, maintenance, and repair." Cold Spring Harb Symp Quant Biol 73 (2008): 291-295. (Review)
PMID
19028985
Source
pubmed
Published In
Cold Spring Harbor Laboratory: Symposia on Quantitative Biology
Volume
73
Publish Date
2008
Start Page
291
End Page
295
DOI
10.1101/sqb.2008.73.037

Summary: Present and future challenges for stem cell research

Stem cell research is being driven forward at an intense pace by creative interactions among scientists working in different fields. These include developmental and reproductive biology, regeneration, genomics, live cell imaging, RNA biology, and cancer biology, to name a few. Numerous model systems and techniques are being exploited, and lab scientists are teaming up with bioengineers and clinicians. The ferment of ideas that makes the field so exciting was in full evidence throughout the Symposium. However, many challenges still need to be overcome to translate basic discoveries into therapeutic outcomes that will save lives and fulfill the promises that have been made. This chapter summarizes some of the highlights of the Symposium and indicates future directions that are being taken by leaders in the field. ©2008 Cold Spring Harbor Laboratory Press.

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "Summary: Present and future challenges for stem cell research." Cold Spring Harbor Symposia on Quantitative Biology 73 (2008): 593-600.
PMID
19329577
Source
scival
Published In
Cold Spring Harbor Laboratory: Symposia on Quantitative Biology
Volume
73
Publish Date
2008
Start Page
593
End Page
600
DOI
10.1101/sqb.2008.73.059

Mouse primordial germ cells: Isolation and in vitro culture

Authors
Labosky, PA; Hogan, BLM
MLA Citation
Labosky, PA, and Hogan, BLM. "Mouse primordial germ cells: Isolation and in vitro culture." Methods in Molecular Biology 461 (2008): 187-199.
PMID
19030797
Source
scival
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
461
Publish Date
2008
Start Page
187
End Page
199
DOI
10.1007/978-1-60327-483-8_12

Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos

E-cadherin is a ubiquitous component of lateral membranes in epithelial tissues and is required to form the first lateral membrane domains in development. Here, we identify ankyrin-G as a molecular partner of E-cadherin and demonstrate that ankyrin-G and β-2-spectrin are required for accumulation of E-cadherin at the lateral membrane in both epithelial cells and early embryos. Ankyrin-G binds to the cytoplasmic domain of E-cadherin at a conserved site distinct from that of β-catenin. Ankyrin-G also recruits β-2-spectrin to E-cadherin-β-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. In addition to restricting the membrane mobility of E-cadherin, ankyrin-G and β-2-spectrin also are required for exit of E-cadherin from the trans-Golgi network in a microtubule-dependent pathway. Ankyrin-G and β-2-spectrin co-localize with E-cadherin in preimplantation mouse embryos. Moreover, knockdown of either ankyrin-G or β-2-spectrin in one cell of a two-cell embryo blocks accumulation of E-cadherin at sites of cell-cell contact. E-cadherin thus requires both ankyrin-G and β-2-spectrin for its cellular localization in early embryos as well as cultured epithelial cells. We have recently reported that ankyrin-G and β-2-spectrin collaborate in biogenesis of the lateral membrane (Kizhatil, K., Yoon, W., Mohler, P. J., Davis, L. H., Hoffman, J. A., and Bennett, V. (2007) J. Biol. Chem. 282, 2029-2037). Together with the current findings, these data suggest a ankyrin/spectrin-based mechanism for coordinating membrane assembly with extracellular interactions of E-cadherin at sites of cell-cell contact. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Kizhatil, K; Davis, JQ; Davis, L; Hoffman, J; Hogan, BLM; Bennett, V
MLA Citation
Kizhatil, K, Davis, JQ, Davis, L, Hoffman, J, Hogan, BLM, and Bennett, V. "Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos." Journal of Biological Chemistry 282.36 (2007): 26552-26561.
PMID
17620337
Source
scival
Published In
The Journal of biological chemistry
Volume
282
Issue
36
Publish Date
2007
Start Page
26552
End Page
26561
DOI
10.1074/jbc.M703158200

A Shared Vision

One of today's most powerful technologies in biomedical research-the creation of mutant mice by gene targeting in embryonic stem (ES) cells-was finally celebrated in this year's Nobel Prize in Medicine. The history of how ES cells were first discovered and genetically manipulated highlights the importance of collaboration among scientists from different backgrounds with a shared vision. © 2007 Elsevier Inc. All rights reserved.

Authors
Hogan, B
MLA Citation
Hogan, B. "A Shared Vision." Developmental Cell 13.6 (2007): 769-771.
PMID
18061560
Source
scival
Published In
Developmental Cell
Volume
13
Issue
6
Publish Date
2007
Start Page
769
End Page
771
DOI
10.1016/j.devcel.2007.11.012

Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells

The miR-17-92 locus encodes a cluster of 7 microRNAs transcribed as a single primary transcript. It can accelerate c-Myc induced B cell lymphoma development and is highly expressed in many tumors, including lung tumors. However, the role of miR-17-92 in development has not been well studied. From analysis of microRNAs during lung development, expression of the miR-17-92 cluster is high at early stages, but declines as development proceeds. We used the mouse surfactant protein C (Sftpc) promoter to over-express the cluster in embryonic lung epithelium. Transgenic lungs have a very abnormal lethal phenotype. They contain numerous proliferative epithelial cells that retain high levels of Sox9, a marker of distal progenitors. The differentiation of proximal epithelial cells was also inhibited. Furthermore, a significant increase in the number of neuroendocrine cell clusters was observed in the lungs of dead transgenic pups. We identify a tumor suppressor, Rbl2 which belongs to the Rb family, as a new target for miR-17-5p. Together, these studies suggest that mir-17-92 normally promotes the high proliferation and undifferentiated phenotype of lung epithelial progenitor cells. © 2007 Elsevier Inc. All rights reserved.

Authors
Lu, Y; Thomson, JM; Wong, HYF; Hammond, SM; Hogan, BLM
MLA Citation
Lu, Y, Thomson, JM, Wong, HYF, Hammond, SM, and Hogan, BLM. "Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells." Developmental Biology 310.2 (2007): 442-453.
PMID
17765889
Source
scival
Published In
Developmental Biology
Volume
310
Issue
2
Publish Date
2007
Start Page
442
End Page
453
DOI
10.1016/j.ydbio.2007.08.007

Retrospective. Anne McLaren (1927-2007).

Authors
Rossant, J; Hogan, B
MLA Citation
Rossant, J, and Hogan, B. "Retrospective. Anne McLaren (1927-2007)." Science (New York, N.Y.) 317.5838 (2007): 609--.
PMID
17673646
Source
scival
Published In
Science
Volume
317
Issue
5838
Publish Date
2007
Start Page
609-
DOI
10.1126/science.1147801

Global gene expression profiling reveals similarities and differences among mouse pluripotent stem cells of different origins and strains

Pluripotent stem cell lines with similar phenotypes can be derived from both blastocysts (embryonic stem cells, ESC) and primordial germ cells (embryonic germ cells, EGC). Here, we present a compendium DNA microarray analysis of multiple mouse ESCs and EGCs from different genetic backgrounds (strains 129 and C57BL/6) cultured under standard conditions and in differentiation-promoting conditions by the withdrawal of Leukemia Inhibitory Factor (LIF) or treatment with retinoic acid (RA). All pluripotent cell lines showed similar gene expression patterns, which separated them clearly from other tissue stem cells with lower developmental potency. Differences between pluripotent lines derived from different sources (ESC vs. EGC) were smaller than differences between lines derived from different mouse strains (129 vs. C57BL/6). Even in the differentiation-promoting conditions, these pluripotent cells showed the same general trends of gene expression changes regardless of their origin and genetic background. These data indicate that ESCs and EGCs are indistinguishable based on global gene expression patterns alone. On the other hand, a detailed comparison between a group of ESC lines and a group of EGC lines identified 20 signature genes whose average expression levels were consistently higher in ESC lines, and 84 signature genes whose average expression levels were consistently higher in EGC lines, irrespective of mouse strains. Similar analysis identified 250 signature genes whose average expression levels were consistently higher in a group of 129 cell lines, and 337 signature genes whose average expression levels were consistently higher in a group of C57BL/6 cell lines. Although none of the genes was exclusively expressed in either ESCs versus EGCs or 129 versus C57BL/6, in combination these signature genes provide a reliable separation and identification of each cell type. Differentiation-promoting conditions also revealed some minor differences between the cell lines. For example, in the presence of RA, EGCs showed a lower expression of muscle- and cardiac-related genes and a higher expression of gonad-related genes than ESCs. Taken together, the results provide a rich source of information about the similarities and differences between ESCs and EGCs as well as 129 lines and C57BL/6 lines. Such information will be crucial to our understanding of pluripotent stem cells. The results also underscore the importance of studying multiple cell lines from different strains when making comparisons based on gene expression analysis. © 2007 Elsevier Inc. All rights reserved.

Authors
Sharova, LV; Sharov, AA; Piao, Y; Shaik, N; Sullivan, T; Stewart, CL; Hogan, BLM; Ko, MSH
MLA Citation
Sharova, LV, Sharov, AA, Piao, Y, Shaik, N, Sullivan, T, Stewart, CL, Hogan, BLM, and Ko, MSH. "Global gene expression profiling reveals similarities and differences among mouse pluripotent stem cells of different origins and strains." Developmental Biology 307.2 (2007): 446-459.
PMID
17560561
Source
scival
Published In
Developmental Biology
Volume
307
Issue
2
Publish Date
2007
Start Page
446
End Page
459
DOI
10.1016/j.ydbio.2007.05.004

Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm

Sox2 is expressed in developing foregut endoderm, with highest levels in the future esophagus and anterior stomach. By contrast, Nkx2.1 (Titf1) is expressed ventrally, in the future trachea. In humans, heterozygosity for SOX2 is associated with anopthalmia-esophageal-genital syndrome (OMIM 600992), a condition including esophageal atresia (EA) and tracheoesophageal fistula (TEF), in which the trachea and esophagus fail to separate. Mouse embryos heterozygous for the null allele, Sox2EGFP, appear normal. However, further reductions in Sox2, using Sox2LP and Sox2COND hypomorphic alleles, result in multiple abnormalities. Approximately 60% of Sox2EGFPICOND embryos have EA with distal TEF in which Sox2 is undetectable by immunohistochemistry or western blot. The mutant esophagus morphologically resembles the trachea, with ectopic expression of Nkx2.1, a columnar, diliated epithelium, and very few p63+ basal cells. By contrast, the abnormal foregut of Nkx2.1-null embryos expresses elevated Sox2 and p63, suggesting reciprocal regulation of Sox2 and Nkx2.1 during early dorsaltventral foregut patterning. Organ culture experiments further suggestthat FGF signaling from the ventral mesenchyme regulates Sox2 expression in the endoderm. In the 40% Sox2EGFPICOND embryos in which Sox2 levels are -18% of wild type there is no TEF. However, the esophagus is still abnormal, with luminal mucus-producing cells, fewer p63+ cells, and ectopic expression of genes normally expressed in glandular stomach and intestine. In all hypomorphic embryos the forestomach has an abnormal phenotype, with reduced keratinization, ectopic mucus cells and columnar epithelium. These findings suggest that Sox2 plays a second role in establishing the boundary between the keratinized, squamous esophagus/ forestomach and glandular hindstomach.

Authors
Que, J; Okubo, T; Goldenring, JR; Nam, K-T; Kurotani, R; Morrisey, EE; Taranova, O; Pevny, LH; Hogan, BLM
MLA Citation
Que, J, Okubo, T, Goldenring, JR, Nam, K-T, Kurotani, R, Morrisey, EE, Taranova, O, Pevny, LH, and Hogan, BLM. "Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm." Development 134.13 (2007): 2521-2531.
PMID
17522155
Source
scival
Published In
Development (Cambridge)
Volume
134
Issue
13
Publish Date
2007
Start Page
2521
End Page
2531
DOI
10.1242/dev.003855

Integrated proteomic and transcriptomic profiling of mouse lung development and Nmyc target genes

Although microarray analysis has provided information regarding the dynamics of gene expression during development of the mouse lung, no extensive correlations have been made to the levels of corresponding protein products. Here, we present a global survey of protein expression during mouse lung organogenesis from embryonic day E13.5 until adulthood using gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry (MudPIT). Mathematical modeling of the proteomic profiles with parallel DNA microarray data identified large groups of gene products with statistically significant correlation or divergence in coregulation of protein and transcript levels during lung development. We also present an integrative analysis of mRNA and protein expression in Nmyc loss- and gain-of-function mutants. This revealed a set of 90 positively and negatively regulated putative target genes. These targets are evidence that Nmyc is a regulator of genes involved in mRNA processing and a repressor of the imprinted gene Igf2r in the developing lung. © 2007 EMBO and Nature Publishing Group All rights reserved.

Authors
Cox, B; Kislinger, T; Wigle, DA; Kannan, A; Brown, K; Okubo, T; Hogan, B; Jurisica, I; Frey, B; Rossant, J; Emili, A
MLA Citation
Cox, B, Kislinger, T, Wigle, DA, Kannan, A, Brown, K, Okubo, T, Hogan, B, Jurisica, I, Frey, B, Rossant, J, and Emili, A. "Integrated proteomic and transcriptomic profiling of mouse lung development and Nmyc target genes." Molecular Systems Biology 3 (2007).
PMID
17486137
Source
scival
Published In
Molecular systems biology
Volume
3
Publish Date
2007
DOI
10.1038/msb4100151

Lung development and repair: Contribution of the ciliated lineage

The identity of the endogenous epithelial cells in the adult lung that are responsible for normal turnover and repair after injury is still controversial. In part, this is due to a paucity of highly specific genetic lineage tools to follow efficiently the fate of the major epithelial cell populations: the basal, secretory, ciliated, neuroendocrine, and alveolar cells. As part of a program to address this problem we have used a 1-kb FOXJ1 promoter to drive CreER in the ciliated cells of the embryonic and adult lung. Analysis of FOXJ1-GFP transgenic lungs shows that labeled cells appear in a proximal-distal pattern during embryogenesis and that the promoter drives expression in all ciliated cells. Using FOXJ1CreER adult mice, we have followed the fate of ciliated cells after epithelial injury by naphthalene or sulfur dioxide. From quantitative analysis and confocal microscopy we conclude that ciliated cells transiently change their morphology in response to lung injury but do not proliferate or transdifferentiate as part of the repair process. © 2006 by The National Academy of Sciences of the USA.

Authors
Rawlins, EL; Ostrowski, LE; Randell, SH; Hogan, BLM
MLA Citation
Rawlins, EL, Ostrowski, LE, Randell, SH, and Hogan, BLM. "Lung development and repair: Contribution of the ciliated lineage." Proceedings of the National Academy of Sciences of the United States of America 104.2 (2007): 410-417.
PMID
17194755
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
2
Publish Date
2007
Start Page
410
End Page
417
DOI
10.1073/pnas.0610770104

Against the ATS statement on human embryonic stem cell research - Reply

Authors
Brown, JK; Ewart, G; Hogan, BLM; Neubauer, J; Randell, SH; Stripp, B; Weiss, DJ
MLA Citation
Brown, JK, Ewart, G, Hogan, BLM, Neubauer, J, Randell, SH, Stripp, B, and Weiss, DJ. "Against the ATS statement on human embryonic stem cell research - Reply." AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 174.3 (August 1, 2006): 357-358.
Source
wos-lite
Published In
American journal of respiratory and critical care medicine
Volume
174
Issue
3
Publish Date
2006
Start Page
357
End Page
358

Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells

Authors
Eblaghie, MC; Reedy, M; Oliver, T; Mishina, Y; Hogan, BLM
MLA Citation
Eblaghie, MC, Reedy, M, Oliver, T, Mishina, Y, and Hogan, BLM. "Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells." DEVELOPMENTAL BIOLOGY 291.1 (March 1, 2006): 67-82.
PMID
16414041
Source
wos-lite
Published In
Developmental Biology
Volume
291
Issue
1
Publish Date
2006
Start Page
67
End Page
82
DOI
10.1016//j.ydbio.2005.12.006

Sox2 is required for development of taste bud sensory cells

Sox2 is expressed in basal epithelial cells of the tongue, with high levels in taste bud placodes, fungiform papillae, and mature taste cells, and low levels in filiform papillae. High Sox2 expression appears to lie downstream from canonical Wnt signaling. In hypomorphic Sox2EGFP/LP embryos, placodes form but no mature taste buds develop. In contrast, transgenic overexpression of Sox2 in the basal cells inhibits differentiation of filiform keratinocytes. Together, our loss-of-function and gain-of-function studies suggest that Sox2 functions in a dose-dependent manner to regulate the differentiation of endodermal progenitor cells of the tongue into taste bud sensory cells versus keratinocytes. © 2006 by Cold Spring Harbor Laboratory Press.

Authors
Okubo, T; Pevny, LH; Hogan, BLM
MLA Citation
Okubo, T, Pevny, LH, and Hogan, BLM. "Sox2 is required for development of taste bud sensory cells." Genes and Development 20.19 (2006): 2654-2659.
PMID
17015430
Source
scival
Published In
Genes & development
Volume
20
Issue
19
Publish Date
2006
Start Page
2654
End Page
2659
DOI
10.1101/gad.1457106

Building organs from buds, branches and tubes

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "Building organs from buds, branches and tubes." Differentiation 74.7 (2006): 323-325.
PMID
16916372
Source
scival
Published In
Differentiation
Volume
74
Issue
7
Publish Date
2006
Start Page
323
End Page
325
DOI
10.1111/j.1432-0436.2006.00107.x

Morphogenesis of the trachea and esophagus: Current players and new roles for noggin and Bmps

The development of the anterior foregut of the mammalian embryo involves changes in the behavior of both the epithelial endoderm and the adjacent mesoderm. Morphogenetic processes that occur include the extrusion of midline notochord cells from the epithelial definitive endoderm, the folding of the endoderm into a foregut tube, and the subsequent separation of the foregut tube into trachea and esophagus. Defects in foregut morphogenesis underlie the constellation of human birth defects known as esophageal atresia (EA) and tracheoesophageal fistula (TEF). Here, we review what is known about the cellular events in foregut morphogenesis and the gene mutations associated with EA and TEF in mice and humans. We present new evidence that about 70% of mouse embryos homozygous null for Nog, the gene encoding noggin, a bone morphogenetic protein (Bmp) antagonist, have EA/TEF as well as defects in lung branching. This phenotype appears to correlate with abnormal morphogenesis of the notochord and defects in its separation from the definitive endoderm. The abnormalities in foregut and lung morphogenesis of Nog null mutant can be rescued by reducing the gene dose of Bmp4 by 50%. This suggests that normal foregut morphogenesis requires that the level of Bmp4 activity is carefully controlled by means of antagonists such as noggin. Several mechanisms are suggested for how Bmps normally function, including by regulating the intercellular adhesion and behavior of notochord and foregut endoderm cells. Future research must determine how Noggin/Bmp antagonism fits into the network of other factors known to regulate tracheal and esophagus development, both in mouse or humans. © 2006, Copyright the Authors.

Authors
Que, J; Choi, M; Ziel, JW; Klingensmith, J; Hogan, BLM
MLA Citation
Que, J, Choi, M, Ziel, JW, Klingensmith, J, and Hogan, BLM. "Morphogenesis of the trachea and esophagus: Current players and new roles for noggin and Bmps." Differentiation 74.7 (2006): 422-437.
PMID
16916379
Source
scival
Published In
Differentiation
Volume
74
Issue
7
Publish Date
2006
Start Page
422
End Page
437
DOI
10.1111/j.1432-0436.2006.00096.x

From the authors [4]

Authors
Brown, JK; Ewart, G; Hogan, BLM; Neubauer, J; Randell, SH; Stripp, B; Weiss, DJ
MLA Citation
Brown, JK, Ewart, G, Hogan, BLM, Neubauer, J, Randell, SH, Stripp, B, and Weiss, DJ. "From the authors [4]." American Journal of Respiratory and Critical Care Medicine 174.3 (2006): 357-358.
Source
scival
Published In
American journal of respiratory and critical care medicine
Volume
174
Issue
3
Publish Date
2006
Start Page
357
End Page
358
DOI
10.1111/j.1475-6773.2005.00485.x

Epithelial stem cells of the lung: Privileged few or opportunities for many?

Most reviews of adult stem cells focus on the relatively undifferentiated cells dedicated to the renewal of rapidly proliferating tissues, such as the skin, gut and blood. By contrast, there is mounting evidence that organs and tissues such as the liver and pancreatic islets, which turn over more slowly, use alternative strategies, including the self-renewal of differentiated cells. The response of these organs to injury may also reveal the potential of differentiated cells to act as stem cells. The lung shows both slow turnover and rapid repair. New experimental approaches, including those based on studies of embryonic development, are needed to identify putative lung stem cells and strategies of lung homeostasis and repair.

Authors
Rawlins, EL; Hogan, BLM
MLA Citation
Rawlins, EL, and Hogan, BLM. "Epithelial stem cells of the lung: Privileged few or opportunities for many?." Development 133.13 (2006): 2455-2465.
PMID
16735479
Source
scival
Published In
Development (Cambridge)
Volume
133
Issue
13
Publish Date
2006
Start Page
2455
End Page
2465
DOI
10.1242/dev.02407

Bmp signaling is required for intestinal growth and morphogenesis

Intestinal growth, morphogenesis, differentiation, and homeostasis are regulated by reciprocal interactions between the epithelium and the underlying mesenchymal stroma. The identification of BMPR1A mutations in patients with Juvenile Polyposis implicates Bmp signaling as an important mediator of these interactions. To test this hypothesis, we inhibited Bmp signalling in the mouse proximal intestine by transgenic misexpression of the BMP antagonist, noggin, using regulatory elements of the fatty acid binding protein (Fabp1) gene. This leads to abnormal villus morphogenesis, stromal and epithelial hyperplasia, and ectopic crypt formation. The resulting intestinal histopathology resembles that seen in human Juvenile Polyposis. Misexpression of noggin in the large intestine gives a similar abnormal phenotype in this region of the gut. Analysis of gene expression in the transgenic small intestine raises the possibility that Hedgehog and Pdgf signaling play a role in the development of the Juvenile Polyposis-like phenotype. © 2006 Wiley-Liss, Inc.

Authors
Batts, LE; Polk, DB; Dubois, RN; Kulessa, H; Hogan, B
MLA Citation
Batts, LE, Polk, DB, Dubois, RN, Kulessa, H, and Hogan, B. "Bmp signaling is required for intestinal growth and morphogenesis." Developmental Dynamics 235.6 (2006): 1563-1570.
PMID
16538672
Source
scival
Published In
Developmental Dynamics
Volume
235
Issue
6
Publish Date
2006
Start Page
1563
End Page
1570
DOI
10.1002/dvdy.20741

Identification of Tgfβ1i4 as a downstream target of Foxc1

Craniofacial development is severely affected by null mutations in Foxc1, indicating a multifunctional role for Foxc1 in ocular, maxilla and mandible, skull and facial gland development. To delineate signaling pathways in which Foxc1 is involved we compared the transcriptomes of whole heads of Foxc1+/+ and Foxc1-/- embryos using a candidate cDNA array comprising genes expressed in the head mesenchyme and ocular region, and a 7K oligo array. Absence of Foxc1 led to downregulation of Stat1 and Galnt4, and upregulation of Tgfβ1i4 at embryonic day 13.5 in the developing head mesenchyme. Comparative analyses revealed differences in the expression pattern of Tgfβ1i4 in the head mesenchyme of Foxc1-/- and Foxc1+/+ embryos. In the ocular regions of Foxc1-/- embryos, Tgfβ1i4 was expressed in higher levels in the conjunctival epithelium and in the condensing mesenchyme on the nasal aspect of the developing eye while in wild-type embryos more intense expression was seen in the mesenchyme on the temporal aspect of the eye. Such data indicate that Foxc1 regulation of Tgfβ1i4 is complex and may be cell-type dependent. Analysis of the regulation of Tgfβ1i4 by Foxc1 in a more homogenous cell population, mesenchymal cells isolated from the periocular region revealed that, in these cells, Foxc1 negatively regulated Tgfβ1i4 expression, presumably via secreted factors such as TGF-β1. Since Foxc1 expression is essential for normal craniofacial development, it is possible that its downstream targets play a role in the development of the phenotypes associated with null mutations in Foxc1. © 2006 The Authors.

Authors
Sommer, P; Napier, HR; Hogan, BL; Kidson, SH
MLA Citation
Sommer, P, Napier, HR, Hogan, BL, and Kidson, SH. "Identification of Tgfβ1i4 as a downstream target of Foxc1." Development Growth and Differentiation 48.5 (2006): 297-308.
PMID
16759280
Source
scival
Published In
Development Growth & Differentiation
Volume
48
Issue
5
Publish Date
2006
Start Page
297
End Page
308
DOI
10.1111/j.1440-169X.2006.00866.x

Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells

Lung development requires reciprocal epithelial/mesenchymal interactions, mediated by signaling factors such as Bmps made in both cell populations. To address the role of Bmp signaling in the epithelium, we have exploited the fact that Bmp receptor type Ia (Alk3) is expressed in the epithelium during branching morphogenesis. Deletion of Bmpr1a in the epithelium with an Sftpc-cre transgene leads to dramatic defects in lung development. There is reduced epithelial proliferation, extensive apoptosis, changes in cell morphology and extrusion of cells into the lumen. By E18.5, there are fewer Type II cells than normal, and the lung contains large fluid-filled spaces. If cell death is prevented by making embryos homozygous null for the proapoptotic gene, Bax, the epithelial cells that are rescued can apparently differentiate, but normal morphogenesis is not restored. To determine whether Bmps made by the epithelium can function in an autocrine manner, mesenchyme-free endoderm was cultured in Matrigel™ with Fgfs. Under these conditions, the mutant epithelium fails to undergo secondary budding. Abnormal development was also seen when Bmp4 was specifically deleted in the epithelium using the Sftpc-cre transgene. Our results support a model in which Bmp signaling primarily regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells. © 2005 Elsevier Inc. All rights reserved.

Authors
Eblaghie, MC; Reedy, M; Oliver, T; Mishina, Y; Hogan, BLM
MLA Citation
Eblaghie, MC, Reedy, M, Oliver, T, Mishina, Y, and Hogan, BLM. "Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells." Developmental Biology 291.1 (2006): 67-82.
Source
scival
Published In
Developmental Biology
Volume
291
Issue
1
Publish Date
2006
Start Page
67
End Page
82
DOI
10.1016/j.ydbio.2005.12.006

The role of the forkhead transcription factor, Foxc1, in the development of the mouse lacrimal gland

The lacrimal gland produces secretions that lubricate and protect the cornea of the eye. Foxc1 encodes a forkhead/winged helix transcription factor required for the development of many embryonic organs. Autosomal dominant mutations in human FOXC1 cause eye disorders such as Axenfeld-Rieger Syndrome and glaucoma iris hypoplasia, resulting from malformation of the anterior segment of the eye. We show here that lacrimal gland development is severely impaired in homozygous null Foxc1 mouse mutants, with reduced outgrowth and branching. Foxc1 is expressed in both the epithelium of the lacrimal gland and the surrounding mesenchyme. FGF10 stimulates the growth and branching morphogenesis in cultures of wild type and Foxc1 mutant gland epithelial buds. However, using micromass culture of lacrimal gland mesenchyme, we show that Bmp7 induces wild type mesenchyme cells to aggregate, but Foxc1 mutant cells do not respond. This study demonstrates that Foxc1 mediates the BMP signaling required for lacrimal gland development. © 2006 Wiley-Liss, Inc.

Authors
Mattiske, D; Sommer, P; Kidson, SH; Hogan, BLM
MLA Citation
Mattiske, D, Sommer, P, Kidson, SH, and Hogan, BLM. "The role of the forkhead transcription factor, Foxc1, in the development of the mouse lacrimal gland." Developmental Dynamics 235.4 (2006): 1074-1080.
PMID
16470615
Source
scival
Published In
Developmental Dynamics
Volume
235
Issue
4
Publish Date
2006
Start Page
1074
End Page
1080
DOI
10.1002/dvdy.20702

CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis

Charged MVB protein 5 (CHMP5) is a coiled coil protein homologous to the yeast Vps60/Mos10 gene and other ESCRT-III complex members, although its precise function in either yeast or mammalian cells is unknown. We deleted the CHMP5 gene in mice, resulting in a phenotype of early embryonic lethality, reflecting defective late endosome function and dysregulation of signal transduction. Chmp5-/- cells exhibit enlarged late endosomal compartments that contain abundant internal vesicles expressing proteins that are characteristic of late endosomes and lysosomes. This is in contrast to ESCRT-III mutants in yeast, which are defective in multivesicular body (MVB) formation. The degradative capacity of Chmp5-/- cells was reduced, and undigested proteins from multiple pathways accumulated in enlarged MVBs that failed to traf. c their cargo to lysosomes. Therefore, CHMP5 regulates late endosome function downstream of MVB formation, and the loss of CHMP5 enhances signal transduction by inhibiting lysosomal degradation of activated receptors. © The Rockefeller University Press.

Authors
Shim, J-H; Xiao, C; Hayden, MS; Lee, K-Y; Trombetta, ES; Pypaert, M; Nara, A; Yoshimori, T; Wilm, B; Erdjument-Bromage, H; Tempst, P; Hogan, BLM; Mellman, I; Ghosh, S
MLA Citation
Shim, J-H, Xiao, C, Hayden, MS, Lee, K-Y, Trombetta, ES, Pypaert, M, Nara, A, Yoshimori, T, Wilm, B, Erdjument-Bromage, H, Tempst, P, Hogan, BLM, Mellman, I, and Ghosh, S. "CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis." Journal of Cell Biology 172.7 (2006): 1045-1056.
PMID
16567502
Source
scival
Published In
The Journal of Cell Biology
Volume
172
Issue
7
Publish Date
2006
Start Page
1045
End Page
1056
DOI
10.1083/jcb.200509041

The mouse forkhead gene Foxc1 is required for primordial germ cell migration and antral follicle development

Foxc1 encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues. Previous studies have investigated defects in the urogenital system of Foxc1 null mutants, but the mechanisms underlying the abnormal development of the gonad have not been explored. From earliest stages, the mutant ovaries are smaller than normal, with fewer germ cells and disorganized somatic issue. No bursa membrane is formed, and the oviduct remains uncoiled. Although germ cells are specified correctly, many of them do not migrate to the gonadal ridge, remaining trapped in the hindgut. Consequently, the number initially reaching the gonad is less than 25% of normal. Once in the ovary, germ cells proliferate normally, but the supporting somatic cells are not organized correctly. Since mutant embryos die at birth, further development was followed in ovaries grafted underneath the kidney capsule of ovariectomized females. Transplanted ovaries display normal folliculogenesis up to preantral stages. However, no follicles develop beyond early antral stages. Mutant follicles are often polyovulatory and have disrupted theca and granulosa cell layers. We conclude that alongside its previously known roles in kidney, cardiovascular and eye development, Foxc1 has essential functions during at least two stages of gonad development-germ cell migration and folliculogenesis. © 2005 Elsevier Inc. All rights reserved.

Authors
Mattiske, D; Kume, T; Hogan, BLM
MLA Citation
Mattiske, D, Kume, T, and Hogan, BLM. "The mouse forkhead gene Foxc1 is required for primordial germ cell migration and antral follicle development." Developmental Biology 290.2 (2006): 447-458.
PMID
16412416
Source
scival
Published In
Developmental Biology
Volume
290
Issue
2
Publish Date
2006
Start Page
447
End Page
458
DOI
10.1016/j.ydbio.2005.12.007

An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production.

Phospholipase C and several inositol polyphosphate kinase (IPK) activities generate a branched ensemble of inositol polyphosphate second messengers that regulate cellular signaling pathways in the nucleus and cytoplasm. Here, we report that mice deficient for Ipk2 (also known as inositol polyphosphate multikinase), an inositol trisphosphate and tetrakisphosphate 6/5/3-kinase active at several places in the inositol metabolic pathways, die around embryonic day 9.5 with multiple morphological defects, including abnormal folding of the neural tube. Metabolic analysis of Ipk2-deficient cells demonstrates that synthesis of the majority of inositol pentakisphosphate, hexakisphosphate and pyrophosphate species are disrupted, although the presence of 10% residual inositol hexakisphosphate indicates the existence of a minor alternative pathway. Agonist induced inositol tris- and bis-phosphate production and calcium release responses are present in homozygous mutant cells, indicating that the observed mouse phenotypes are a result of failure to produce higher inositol polyphosphates. Our data demonstrate that Ipk2 plays a major role in the synthesis of inositol polyphosphate messengers derived from inositol 1,4,5-trisphosphate and uncovers a role for their production in embryogenesis and normal development.

Authors
Frederick, JP; Mattiske, D; Wofford, JA; Megosh, LC; Drake, LY; Chiou, S-T; Hogan, BLM; York, JD
MLA Citation
Frederick, JP, Mattiske, D, Wofford, JA, Megosh, LC, Drake, LY, Chiou, S-T, Hogan, BLM, and York, JD. "An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production." Proc Natl Acad Sci U S A 102.24 (June 14, 2005): 8454-8459.
PMID
15939867
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
102
Issue
24
Publish Date
2005
Start Page
8454
End Page
8459
DOI
10.1073/pnas.0503706102

Intercellular growth factor signaling and the development of mouse tracheal submucosal glands

To provide a genetic framework for investigating changes in airway submucosal gland function in human respiratory disease, we have investigated their counterparts in normal and mutant mice. We describe their morphogenesis in relation to the expression of genes encoding conserved intercellular signaling pathways. Submucosal glands are severely reduced in number and size in mice heterozygous for Fgf10. Glands are completely absent in mice lacking Ectodysplasin (Eda) and Edaradd (Eda receptor adaptor protein), members of the tumor necrosis (TNF) superfamily of signaling factors. Furthermore, components of the Eda and closely related pathways are transcribed throughout the respiratory system in the adult mouse. Finally, the temporal and spatial pattern of Bmp4 expression suggests that it may control submucosal gland development and homeostasis. Taken together, our observations have important implications for the better understanding of the submucosal gland remodeling that occurs in human respiratory disease. © 2005 Wiley-Liss, Inc.

Authors
Rawlins, EL; Hogan, BLM
MLA Citation
Rawlins, EL, and Hogan, BLM. "Intercellular growth factor signaling and the development of mouse tracheal submucosal glands." Developmental Dynamics 233.4 (2005): 1378-1385.
PMID
15973734
Source
scival
Published In
Developmental Dynamics
Volume
233
Issue
4
Publish Date
2005
Start Page
1378
End Page
1385
DOI
10.1002/dvdy.20461

Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation

Understanding how lung progenitor cells balance proliferation against differentiation is relevant to clinical disorders such as bronchopulmonary dysplasia of premature babies and lung cancer. Previous studies have established that lung development is severely disrupted in mouse mutants with reduced levels of the proto-oncogene Nmyc, but the precise mechanisms involved have not been explored. We show here that Nmyc expression in the embryonic lung is normally restricted to a distal population of undifferentiated epithelial cells, a high proportion of which are in the S phase of the cell cycle. Overexpression of NmycEGFP in the epithelium under the control of surfactant protein C (Sftpc) regulatory elements expands the domain of S phase cells and upregulates numerous genes associated with growth and metabolism, as shown by transcriptional microarray. In addition, there is marked inhibition of differentiation, coupled with an expanded domain of expression of Sox9 protein, which is also normally restricted to the distal epithelial compartment. By contrast, conditional deletion of Nmyc leads to reduced proliferation, epithelial differentiation and high levels of apoptosis in both epithelium and mesenchyme. Unexpectedly, about 50% of embryos in which only one copy of Nmyc is deleted die perinatally, with similarly abnormal lungs. We propose a model in which Nmyc is essential in the developing lung for maintaining a distal population of undifferentiated, proliferating progenitor cells.

Authors
Okubo, T; Knoepfler, PS; Eisenman, RN; Hogan, BLM
MLA Citation
Okubo, T, Knoepfler, PS, Eisenman, RN, and Hogan, BLM. "Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation." Development 132.6 (2005): 1363-1374.
PMID
15716345
Source
scival
Published In
Development
Volume
132
Issue
6
Publish Date
2005
Start Page
1363
End Page
1374
DOI
10.1242/dev.01678

Handbook of Stem Cells

© 2004 Elsevier Inc. All rights reserved.New discoveries in the field of stem cell research have frequently appeared in the news and in scientific literature. Research in this area promises to lead to new therapies for cancer, heart disease, diabetes, and a wide variety of other diseases. This two-volume reference integrates this exciting area of biology, combining the prerequisites for a general understanding of adult and embryonic stem cells, the tools, methods, and experimental protocols needed to study and characterize stem cells and progenitor populations, as well as a presentation by the worlds experts of what is currently known about each specific organ system. The editors of the Handbook of Stem Cells include: Robert Lanza, Helen Blau, John Gearhart, Brigid Hogan, Douglas Melton, Malcolm Moore, Roger Pedersen, E. Donnall Thomas, James Thomson, Catherine Verfaillie, Irving Weissman, and Michael West. The Editorial Board includes: W. French Anderson, Peter Andrews, Anthony Atala, Jose Cibelli, Giulio Cossu, Robert Edwards, Martin Evans, Elaine Fuchs, Margaret Fuller, Fred Gage, Richard Gardner, Margaret Goodell, Ronald Green, William Haseltine, Joseph Itskovitz-Eldor, Rudolf Jaenisch, Ihor Lemischka, Dame Anne McLaren, Richard Mulligan, Stuart Orkin, Martin Pera, Benjamin Reubinoff, Janet Rossant, Hans Scholer, Austin Smith, Evan Snyder, Davor Solter, Alan Trounson, and Leonard Zon. This comprehensive set should be a much-needed addition to the library of students and researchers alike.

Authors
Lanza, R; Gearhart, J; Hogan, B; Melton, D; Pedersen, R; Thomson, J; West, M
MLA Citation
Lanza, R, Gearhart, J, Hogan, B, Melton, D, Pedersen, R, Thomson, J, and West, M. "Handbook of Stem Cells." Handbook of Stem Cells 1-2 (September 14, 2004): 1-1760.
Source
scopus
Published In
Handbook of Stem Cells
Volume
1-2
Publish Date
2004
Start Page
1
End Page
1760

Novel role for Netrins in regulating epithelial behavior during lung branching morphogenesis.

The development of many organs, including the lung, depends upon a process known as branching morphogenesis, in which a simple epithelial bud gives rise to a complex tree-like system of tubes specialized for the transport of gas or fluids. Previous studies on lung development have highlighted a role for fibroblast growth factors (FGFs), made by the mesodermal cells, in promoting the proliferation, budding, and chemotaxis of the epithelial endoderm. Here, by using a three-dimensional culture system, we provide evidence for a novel role for Netrins, best known as axonal guidance molecules, in modulating the morphogenetic response of lung endoderm to exogenous FGFs. This effect involves inhibition of localized changes in cell shape and phosphorylation of the intracellular mitogen-activated protein kinase(s) (ERK1/2, for extracellular signal-regulated kinase-1 and -2), elicited by exogenous FGFs. The temporal and spatial expression of netrin 1, netrin 4, and Unc5b genes and the localization of Netrin-4 protein in vivo suggest a model in which Netrins in the basal lamina locally modulate and fine-tune the outgrowth and shape of emergent epithelial buds.

Authors
Liu, Y; Stein, E; Oliver, T; Li, Y; Brunken, WJ; Koch, M; Tessier-Lavigne, M; Hogan, BLM
MLA Citation
Liu, Y, Stein, E, Oliver, T, Li, Y, Brunken, WJ, Koch, M, Tessier-Lavigne, M, and Hogan, BLM. "Novel role for Netrins in regulating epithelial behavior during lung branching morphogenesis." Curr Biol 14.10 (May 25, 2004): 897-905.
PMID
15186747
Source
pubmed
Published In
Current Biology
Volume
14
Issue
10
Publish Date
2004
Start Page
897
End Page
905
DOI
10.1016/j.cub.2004.05.020

Novel role for netrins in regulating epithelial behavior during lung branching morphogenesis

Authors
Liu, Y; Stein, E; Oliver, T; Li, Y; Brunken, WJ; Koch, M; Tessier-Lavigne, M; Hogan, BLM
MLA Citation
Liu, Y, Stein, E, Oliver, T, Li, Y, Brunken, WJ, Koch, M, Tessier-Lavigne, M, and Hogan, BLM. "Novel role for netrins in regulating epithelial behavior during lung branching morphogenesis." CURRENT BIOLOGY 14.10 (May 25, 2004): 897-905.
Source
wos-lite
Published In
Current Biology
Volume
14
Issue
10
Publish Date
2004
Start Page
897
End Page
905
DOI
10.1016/j.cub.2004.02.020

The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate mesoderm cell fate

During vertebrate embryogenesis, the newly formed mesoderm is allocated to the paraxial, intermediate, and lateral domains, each giving rise to different cell and tissue types. Here, we provide evidence that the forkhead genes, Foxc1 and Foxc2, play a role in the specification of mesoderm to paraxial versus intermediate fates. Mouse embryos lacking both Foxc1 and Foxc2 show expansion of intermediate mesoderm markers into the paraxial domain, lateralization of somite patterning, and ectopic and disorganized mesonephric tubules. In gain of function studies in the chick embryo, Foxc1 and Foxc2 negatively regulate intermediate mesoderm formation. By contrast, their misexpression in the prospective intermediate mesoderm appears to drive cells to acquire paraxial fate, as revealed by expression of the somite markers Pax7 and Paraxis. Taken together, the data indicate that Foxc1 and Foxc2 regulate the establishment of paraxial versus intermediate mesoderm cell fates in the vertebrate embryo. © 2004 Elsevier Inc. All rights reserved.

Authors
Wilm, B; James, RG; Schultheiss, TM; Hogan, BLM
MLA Citation
Wilm, B, James, RG, Schultheiss, TM, and Hogan, BLM. "The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate mesoderm cell fate." Developmental Biology 271.1 (2004): 176-189.
PMID
15196959
Source
scival
Published In
Developmental Biology
Volume
271
Issue
1
Publish Date
2004
Start Page
176
End Page
189
DOI
10.1016/j.ydbio.2004.03.034

Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm

Background: Studies in many model systems have shown that canonical signaling through the pathway downstream of ligands of the Wnt family can regulate multiple steps in organogenesis, including cell proliferation, differentiation, and lineage specification. In addition, misexpression of the Wnt-family member Wingless in Drosophila imaginal disc cells can lead to transdetermination of progenitors from one lineage to another. Conditional deletion of the β-catenin component of the Wnt signaling pathway has indicated a role for Wnt signaling in mouse lung endoderm development. The full range of effects of this pathway, which includes the transcription factor Lef1, has not been explored, however. Results: To explore this issue, we expressed a constitutively active β-catenin-Lef1 fusion protein in transgenic embryos using a lung-endoderm-specific promoter from the surfactant protein C gene. Transgenic lungs appeared grossly normal, but internally they contained highly proliferative, cuboidal epithelium lacking fully differentiated lung cell types. Unexpectedly, microarray analysis and in situ hybridization revealed a mosaic of cells expressing marker genes characteristic of intestinal Paneth and goblet cells and other non-lung secretory cell types. In addition, there was strong ectopic expression of genes such as Cdx1 and Atoh1 that normally regulate gut development and early allocation of cells to intestinal secretory lineages. Conclusions: Our results show that hyperactive Wnt signaling in lung progenitors expressing a lung-specific gene can induce a dramatic switch in lineage commitment and the generation of intestinal cell types. We discuss the relevance of our findings to the poorly understood pathological condition of intestinal metaplasia in humans.

Authors
Okubo, T; Hogan, BLM
MLA Citation
Okubo, T, and Hogan, BLM. "Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm." Journal of Biology 3.3 (2004).
PMID
15186480
Source
scival
Published In
Journal of Biology
Volume
3
Issue
3
Publish Date
2004
DOI
10.1186/jbiol3

Deconstructing the genesis of animal form

Santa Fe - with its museums and galleries full of art and crafts inspired by natural forms - was the perfect setting for a Keystone conference on vertebrate organogenesis in February 2004. Organized by Gail Martin and Cliff Tabin, the conference sessions were loosely subdivided into anatomical systems - 'skin, hair, teeth', 'pancreas, liver, gut', 'skeleton', and so on. However, from the outset, common themes emerged that transcended particular organ systems and generated a sense of unity and excitement among the participants.

Authors
Hogan, B
MLA Citation
Hogan, B. "Deconstructing the genesis of animal form." Development 131.11 (2004): 2515-2520.
PMID
15148298
Source
scival
Published In
Development
Volume
131
Issue
11
Publish Date
2004
Start Page
2515
End Page
2520
DOI
10.1242/dev.01192

Transcriptome analysis of mouse stem cells and early embryos.

Understanding and harnessing cellular potency are fundamental in biology and are also critical to the future therapeutic use of stem cells. Transcriptome analysis of these pluripotent cells is a first step towards such goals. Starting with sources that include oocytes, blastocysts, and embryonic and adult stem cells, we obtained 249,200 high-quality EST sequences and clustered them with public sequences to produce an index of approximately 30,000 total mouse genes that includes 977 previously unidentified genes. Analysis of gene expression levels by EST frequency identifies genes that characterize preimplantation embryos, embryonic stem cells, and adult stem cells, thus providing potential markers as well as clues to the functional features of these cells. Principal component analysis identified a set of 88 genes whose average expression levels decrease from oocytes to blastocysts, stem cells, postimplantation embryos, and finally to newborn tissues. This can be a first step towards a possible definition of a molecular scale of cellular potency. The sequences and cDNA clones recovered in this work provide a comprehensive resource for genes functioning in early mouse embryos and stem cells. The nonrestricted community access to the resource can accelerate a wide range of research, particularly in reproductive and regenerative medicine.

Authors
Sharov, AA; Piao, Y; Matoba, R; Dudekula, DB; Qian, Y; VanBuren, V; Falco, G; Martin, PR; Stagg, CA; Bassey, UC; Wang, Y; Carter, MG; Hamatani, T; Aiba, K; Akutsu, H; Sharova, L; Tanaka, TS; Kimber, WL; Yoshikawa, T; Jaradat, SA; Pantano, S; Nagaraja, R; Boheler, KR; Taub, D; Hodes, RJ; Longo, DL; Schlessinger, D; Keller, J; Klotz, E; Kelsoe, G; Umezawa, A; Vescovi, AL; Rossant, J; Kunath, T; Hogan, BLM; Curci, A; D'Urso, M; Kelso, J; Hide, W; Ko, MSH
MLA Citation
Sharov, AA, Piao, Y, Matoba, R, Dudekula, DB, Qian, Y, VanBuren, V, Falco, G, Martin, PR, Stagg, CA, Bassey, UC, Wang, Y, Carter, MG, Hamatani, T, Aiba, K, Akutsu, H, Sharova, L, Tanaka, TS, Kimber, WL, Yoshikawa, T, Jaradat, SA, Pantano, S, Nagaraja, R, Boheler, KR, Taub, D, Hodes, RJ, Longo, DL, Schlessinger, D, Keller, J, Klotz, E, Kelsoe, G, Umezawa, A, Vescovi, AL, Rossant, J, Kunath, T, Hogan, BLM, Curci, A, D'Urso, M, Kelso, J, Hide, W, and Ko, MSH. "Transcriptome analysis of mouse stem cells and early embryos." PLoS Biol 1.3 (December 2003): E74-.
PMID
14691545
Source
pubmed
Published In
PLoS biology
Volume
1
Issue
3
Publish Date
2003
Start Page
E74
DOI
10.1371/journal.pbio.0000074

Role for ETS domain transcription factors Pea3/Erm in mouse lung development.

During the development of the mouse lung, the expression of a number of genes, including those encoding growth factors and components of their downstream signaling pathways, is enriched in the epithelium and/or mesenchyme of the distal buds. In this location, they regulate processes such as cell proliferation, branching morphogenesis, and the differentiation of specialized cell types. Here, we report that the expression of Pea3 and Erm (or Etv5, Ets variant gene 5), which encode Pea3 subfamily ETS domain transcription factors, is initially restricted to the distal buds of the developing mouse lung. Erm is transcribed exclusively in the epithelium, while Pea3 is expressed in both epithelium and mesenchyme. Erm/Pea3 are downstream of FGF signaling from the mesenchyme, but their responses toward different FGFs are not the same. The functions of the two proteins were investigated by transgenic expression of a repressor form of Erm specifically in the embryonic lung epithelium. When examined at E18.5, the distal epithelium of transgenic lungs is composed predominantly of immature type II cells, while no mature type I cells are observed. In contrast, the differentiation of proximal epithelial cells, including ciliated cells and Clara cells, appears to be unaffected. A model is proposed for the role of Pea3/Erm during the dynamic process of lung bud outgrowth and proximal-distal differentiation, in response to FGF signaling. Our results provide the first functional evidence that Pea3 subfamily members play a role in epithelial-mesenchymal interactions during lung organogenesis.

Authors
Liu, Y; Jiang, H; Crawford, HC; Hogan, BLM
MLA Citation
Liu, Y, Jiang, H, Crawford, HC, and Hogan, BLM. "Role for ETS domain transcription factors Pea3/Erm in mouse lung development." Dev Biol 261.1 (September 1, 2003): 10-24.
PMID
12941618
Source
pubmed
Published In
Developmental Biology
Volume
261
Issue
1
Publish Date
2003
Start Page
10
End Page
24

An essential role of Bmp4 in the atrioventricular septation of the mouse heart

Proper septation and valvulogenesis during cardiogenesis depend on interactions between the myocardium and the endocardium. By combining use of a hypomorphic Bone morphogenetic protein 4 (Bmp4) allele with conditional gene inactivation, we here identify Bmp4 as a signal from the myocardium directly mediating atrioventricular septation. Defects in this process cause one of the most common human congenital heart abnormalities, atrioventricular canal defect (AVCD). The spectrum of defects obtained through altering Bmp4 expression in the myocardium recapitulates the range of AVCDs diagnosed in patients, thus providing a useful genetic model with AVCD as the primary defect.

Authors
Jiao, K; Kulessa, H; Tompkins, K; Zhou, Y; Batts, L; Baldwin, HS; Hogan, BLM
MLA Citation
Jiao, K, Kulessa, H, Tompkins, K, Zhou, Y, Batts, L, Baldwin, HS, and Hogan, BLM. "An essential role of Bmp4 in the atrioventricular septation of the mouse heart." Genes and Development 17.19 (2003): 2362-2367.
PMID
12975322
Source
scival
Published In
Genes and Development
Volume
17
Issue
19
Publish Date
2003
Start Page
2362
End Page
2367
DOI
10.1101/gad.1124803

Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis

Bone morphogenetic proteins (Bmps) are members of the transforming growth factor β (TGFβ) superfamily that play critical roles during mouse embryogenesis. Signaling by Bmp receptors is mediated mainly by Smad proteins. In this study, we show that a targeted null mutation of Ecsit, encoding a signaling intermediate of the Toll pathway, leads to reduced cell proliferation, altered epiblast patterning, impairment of mesoderm formation, and embryonic lethality at embryonic day 7.5 (E7.5), phenotypes that mimic the Bmp receptor type1a (Bmpr1a) null mutant. In addition, specific Bmp target gene expression is abolished in the absence of Ecsit. Biochemical analysis demonstrates that Ecsit associates constitutively with Smad4 and associates with Smad1 in a Bmp-inducible manner. Together with Smad1 and Smad4, Ecsit binds to the promoter of specific Bmp target genes. Finally, knock-down of Ecsit with Ecsit-specific short hairpin RNA inhibits both Bmp and Toll signaling. Therefore, these results show that Ecsit functions as an essential component in two important signal transduction pathways and establishes a novel role for Ecsit as a cofactor for Smad proteins in the Bmp signaling pathway.

Authors
Xiao, C; Shim, J-H; Klüppel, M; Zhang, SS-M; Dong, C; Flavell, RA; Fu, X-Y; Wrana, JL; Hogan, BLM; Ghosh, S
MLA Citation
Xiao, C, Shim, J-H, Klüppel, M, Zhang, SS-M, Dong, C, Flavell, RA, Fu, X-Y, Wrana, JL, Hogan, BLM, and Ghosh, S. "Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis." Genes and Development 17.23 (2003): 2933-2949.
PMID
14633973
Source
scival
Published In
Genes and Development
Volume
17
Issue
23
Publish Date
2003
Start Page
2933
End Page
2949
DOI
10.1101/gad.1145603

Tissue interactions pattern the mesenchyme of the embryonic mouse lung

The mechanisms that control proliferation and differentiation of embryonic lung mesenchyme are largely unknown. We describe an explant system in which exogenous recombinant N-Sonic Hedgehog (N-Shh) protein sustains the survival and proliferation of lung mesenchyme in a dose-dependent manner. In addition, Shh upregulates several mesenchymal cell markers, including its target gene Patched (Ptc), intercellular signaling genes Bone Morphogenetic Protein-4 (Bmp4) and Noggin (Nog), and smooth muscle actin and myosin. In explants exposed to N-Shh in the medium, these products are upregulated throughout the mesenchyme, but not in the periphery. This exclusion zone correlates with the presence of an overlying mesothelial layer, which, as in vivo, expresses Fibroblast Growth Factor 9 (Fgf9). Recombinant Fgf9 protein inhibits the differentiation response of the mesenchyme to N-Shh, but does not affect proliferation. We propose a model for how factors made by two epithelial cell populations, the inner endoderm and the outer jacket of mesothelium, coordinately regulate the proliferation and differentiation of the lung mesoderm. © 2003 Elsevier Science (USA). All rights reserved.

Authors
Weaver, M; Batts, L; Hogan, BLM
MLA Citation
Weaver, M, Batts, L, and Hogan, BLM. "Tissue interactions pattern the mesenchyme of the embryonic mouse lung." Developmental Biology 258.1 (2003): 169-184.
PMID
12781691
Source
scival
Published In
Developmental Biology
Volume
258
Issue
1
Publish Date
2003
Start Page
169
End Page
184
DOI
10.1016/S0012-1606(03)00117-9

Developmentally regulated expression of two members of the Nrarp family in zebrafish

Delta-Notch signaling is essential for somitogenesis in vertebrate embryos. In a search for genes that control somite formation in zebrafish we have identified two paralogues encoding proteins related to Nrarp (Notch regulated ankyrin repeat protein). Zebrafish nrarp-a and- b encode small proteins with two ankyrin repeat domains. Here, we report the expression patterns of both genes in normal and mutant embryos. © 2003 Elsevier Science B.V. All rights reserved.

Authors
Topczewska, JM; Topczewski, J; Szostak, A; Solnica-Krezel, L; Hogan, BLM
MLA Citation
Topczewska, JM, Topczewski, J, Szostak, A, Solnica-Krezel, L, and Hogan, BLM. "Developmentally regulated expression of two members of the Nrarp family in zebrafish." Gene Expression Patterns 3.2 (2003): 169-171.
PMID
12711545
Source
scival
Published In
Gene Expression Patterns
Volume
3
Issue
2
Publish Date
2003
Start Page
169
End Page
171
DOI
10.1016/S1567-133X(03)00009-7

BMP ligands act redundantly to pattern the dorsal telencephalic midline

The embryonic telencephalon is patterned into several areas that give rise to functionally distinct structures in the adult forebrain. Previous studies have shown that BMP4 and BMP2 can induce features characteristic of the telencephalic midline in cultured explants, suggesting that the normal role of BMP4 in the forebrain is to pattern the medial lateral axis of the telencephalon by promoting midline cell fates. To test this hypothesis directly in vivo, the Bmp4 gene was efficiently disrupted in the telencephalon using a CRE/loxP approach. Analysis of Bmp4-deficient telencephalons fails to reveal a defect in patterning, cell proliferation, differentiation, or apoptosis. The absence of a phenotype in the Bmp4-deficient telencephalon along with recent genetic studies establishing a role for a BMP4 receptor, BMPRIA, in telencephalic midline development, demonstrate that loss of Bmp4 function in the telencephalon can be compensated for by at least one other Bmp gene, the identity of which has not yet been determined. © 2003 Wiley-Liss, Inc.

Authors
Hébert, JM; Hayhurst, M; Marks, ME; Kulessa, H; Hogan, BLM; McConnell, SK
MLA Citation
Hébert, JM, Hayhurst, M, Marks, ME, Kulessa, H, Hogan, BLM, and McConnell, SK. "BMP ligands act redundantly to pattern the dorsal telencephalic midline." Genesis 35.4 (2003): 214-219.
PMID
12717732
Source
scival
Published In
Genesis
Volume
35
Issue
4
Publish Date
2003
Start Page
214
End Page
219
DOI
10.1002/gene.10183

Identification of mZnf8, a mouse Krüppel-like transcriptional repressor, as a novel nuclear interaction partner of Smad1.

To identify novel genes that play critical roles in mediating bone morphogenetic protein (BMP) signal pathways, we performed a yeast two-hybrid screen using Smad1 as bait. A novel mouse Krüppel-type zinc finger protein, mZnf8, was isolated. Interactions between mZnf8 and Smad proteins were further analyzed with various in vitro and in vivo approaches, including mammalian two-hybrid, in vitro glutathione S-transferase pulldown, and copurification assays. Results from functional analysis indicate that mZnf8 is a nuclear transcriptional repressor. Overexpression of mZnf8 represses activity of BMP and transforming growth factor beta (TGF-beta) reporters. Silencing the expression of endogenous mZnf8 with an RNA interference approach caused a significant increase in the expression of one BMP reporter. These results suggest that mZnf8 negatively regulates the TGF-beta/BMP signaling pathway in vivo. Transcription of mZnf8 is ubiquitous in mouse embryos, but high levels are specifically observed in adult mouse testes, with the same cell- and stage-specific transcription pattern as Smad1. Our data support the hypothesis that mZnf8 plays critical roles in mediating BMP signaling during spermatogenesis.

Authors
Jiao, K; Zhou, Y; Hogan, BLM
MLA Citation
Jiao, K, Zhou, Y, and Hogan, BLM. "Identification of mZnf8, a mouse Krüppel-like transcriptional repressor, as a novel nuclear interaction partner of Smad1." Mol Cell Biol 22.21 (November 2002): 7633-7644.
PMID
12370310
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
22
Issue
21
Publish Date
2002
Start Page
7633
End Page
7644

Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse.

In the mouse and chick embryo, the node plays a central role in generating left-right (LR) positional information. Using several different strategies, we provide evidence in the mouse that bone morphogenetic protein 4 (Bmp4) is required independently in two different sites for node morphogenesis and for LR patterning. Bmp4 expression in the trophoblast-derived extra-embryonic ectoderm is essential for the normal formation of the node and primitive streak. However, tetraploid chimera analysis demonstrates that Bmp4 made in epiblast-derived tissues is required for robust LR patterning, even when normal node morphology is restored. In the absence of embryonic Bmp4, the expression of left-side determinants such as Nodal and Lefty2 is absent in the left lateral plate mesoderm (LPM). Noggin-mediated inhibition of Bmp activity in cultured wild-type embryos results in suppression of Nodal expression in the LPM. Thus, unlike previous models proposed in the chick embryo in which Bmp4 suppresses left-sided gene expression, our results suggest that Bmp acts as a positive facilitator of the left-sided molecular cascade and is required for Nodal induction and maintenance in the left LPM.

Authors
Fujiwara, T; Dehart, DB; Sulik, KK; Hogan, BLM
MLA Citation
Fujiwara, T, Dehart, DB, Sulik, KK, and Hogan, BLM. "Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse." Development 129.20 (October 2002): 4685-4696.
PMID
12361961
Source
pubmed
Published In
Development (Cambridge)
Volume
129
Issue
20
Publish Date
2002
Start Page
4685
End Page
4696

Organogenesis: molecular mechanisms of tubulogenesis.

As organisms have evolved in size and complexity, tubular systems have developed to enable the efficient transport of substances into and out of tissues. These tubular systems are generated using strategies that are based on common elements of cell behaviour, including cell polarization, tube migration to target sites, cell-fate diversification and localization of specialized cells to different regions of the tube system. Using examples from both invertebrate and vertebrate systems, this review highlights progress in understanding these basic principles and briefly discusses the possible evolution of strategies to regulate the morphogenesis of tubular systems.

Authors
Hogan, BLM; Kolodziej, PA
MLA Citation
Hogan, BLM, and Kolodziej, PA. "Organogenesis: molecular mechanisms of tubulogenesis." Nat Rev Genet 3.7 (July 2002): 513-523. (Review)
PMID
12094229
Source
pubmed
Published In
Nature Reviews Genetics
Volume
3
Issue
7
Publish Date
2002
Start Page
513
End Page
523
DOI
10.1038/nrg840

Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus.

Genes encoding components of the hedgehog signaling pathway are dynamically expressed in the mouse uterus preparing for implantation. Indian hedgehog (Ihh), patched (Ptc), and Gli3 are expressed at low levels in the endometrial epithelium on day 1 of pregnancy. Transcription of Ihh increases dramatically in the luminal epithelium and glands from day 3, reaching very high levels on day 4. Over the same period, Ptc, Gli1, Gli2, and noggin are strongly upregulated in the underlying mesenchymal stroma. Transcription of Ihh in ovariectomized mice is induced by progesterone but not by estrogen. Lower induction of Ihh, Ptc, and Hoxa10 is seen in response to progesterone in the uteri of Pgr(-/-) mutant mice lacking progesterone nuclear steroid receptor. This finding suggests that the hormone may regulate Ihh through both nuclear receptor-dependent and -independent pathways. We describe a method for culturing uterine explants in the absence of epithelium. Under these conditions, recombinant N-SHH protein promotes the proliferation of mesenchyme cells and the expression of noggin. We propose that IHH made by the epithelium normally functions as a paracrine growth factor for stromal cells during the early stages of pregnancy.

Authors
Matsumoto, H; Zhao, X; Das, SK; Hogan, BLM; Dey, SK
MLA Citation
Matsumoto, H, Zhao, X, Das, SK, Hogan, BLM, and Dey, SK. "Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus." Dev Biol 245.2 (May 15, 2002): 280-290.
PMID
11977981
Source
pubmed
Published In
Developmental Biology
Volume
245
Issue
2
Publish Date
2002
Start Page
280
End Page
290
DOI
10.1006/dbio.2002.0645

Generation of a loxP flanked bmp4loxP-lacZ allele marked by conditional lacZ expression.

Authors
Kulessa, H; Hogan, BLM
MLA Citation
Kulessa, H, and Hogan, BLM. "Generation of a loxP flanked bmp4loxP-lacZ allele marked by conditional lacZ expression." Genesis 32.2 (February 2002): 66-68.
PMID
11857779
Source
pubmed
Published In
Genesis: the Journal of Genetics and Development
Volume
32
Issue
2
Publish Date
2002
Start Page
66
End Page
68

Differential gene expression in the distal tip endoderm of the embryonic mouse lung

During the early development of the mouse lung a number of genes encoding signaling molecules are differentially expressed in the epithelium and mesenchyme of the distal buds. Evidence suggests they play a role in regulating the stereotypic processes of bud outgrowth and branching as well as proximal-distal patterning of both cell layers. To better understand the mechanisms underlying branching morphogenesis, a subtractive hybridization and differential screen was carried out for genes preferentially expressed in the epithelium at the tips of embryonic day 11.5 lung buds, versus more proximal regions. Twenty genes were identified, assigned to different categories based on sequence analysis, and their distal expression confirmed by whole-mount in situ hybridization. © 2002 Elsevier Science B.V. All rights reserved.

Authors
Liu, Y; Hogan, BLM
MLA Citation
Liu, Y, and Hogan, BLM. "Differential gene expression in the distal tip endoderm of the embryonic mouse lung." Gene Expression Patterns 2.3-4 (2002): 229-233.
PMID
12617806
Source
scival
Published In
Gene Expression Patterns
Volume
2
Issue
3-4
Publish Date
2002
Start Page
229
End Page
233
DOI
10.1016/S1567-133X(02)00057-1

Developmental biology: Decisions, decisions!

Early embryo cells can develop either into specialized body cells or into precursors of eggs or sperm. It is not understood how this crucial decision is made in mammals, but new work brings us closer to the answer.

Authors
Hogan, B
MLA Citation
Hogan, B. "Developmental biology: Decisions, decisions!." Nature 418.6895 (2002): 282-283.
PMID
12124605
Source
scival
Published In
Nature
Volume
418
Issue
6895
Publish Date
2002
Start Page
282
End Page
283
DOI
10.1038/418282a

Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse.

Evidence suggests that the specification of primordial germ cells (PGCs) in the mammalian embryo does not depend on maternal determinants. Rather, previous genetic analysis in the mouse has shown that bone morphogenetic protein 4 (Bmp4) is required for the formation of both PGCs and allantois. Bmp4 is expressed in both the trophoblast-derived extraembryonic ectoderm (ExE) and in the epiblast-derived extraembryonic mesoderm (ExM), in which the PGCs, allantois primordium, and angioblasts are first detected. We have shown that Bmp4 made in the ExE functions to induce precursors of PGCs and allantois in the adjacent epiblast, resulting in complete lack of both cell types in homozygous null mutants. However, the function of Bmp4 in the ExM is totally unknown. To address this question, we generated tetraploid (4N) chimeras by aggregating Bmp4 null ES cells with wild-type tetraploid embryos. In this combination, wild-type tetraploid cells contribute to the extraembryonic trophoblast and primitive endoderm lineages but are excluded from the epiblast and its derivatives, including the ExM. Our results clearly demonstrate that Bmp4 made in the ExM does not affect the establishment of either PGC or allantois lineages, but is required for PGC localization and survival and for the differentiation of the allantois. These findings suggest that Bmp4 expressed in epiblast-derived tissues plays vital roles in reproduction by regulating both the development of the germ line and the vascular connection between the embryo and the placenta.

Authors
Fujiwara, T; Dunn, NR; Hogan, BL
MLA Citation
Fujiwara, T, Dunn, NR, and Hogan, BL. "Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse." Proc Natl Acad Sci U S A 98.24 (November 20, 2001): 13739-13744.
PMID
11707591
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
24
Publish Date
2001
Start Page
13739
End Page
13744
DOI
10.1073/pnas.241508898

The winged helix transcription factor Foxc1a is essential for somitogenesis in zebrafish.

Previous studies identified zebrafish foxc1a and foxc1b as homologs of the mouse forkhead gene, Foxc1. Both genes are transcribed in the unsegmented presomitic mesoderm (PSM), newly formed somites, adaxial cells, and head mesoderm. Here, we show that inhibiting synthesis of Foxc1a (but not Foxc1b) protein with two different morpholino antisense oligonucleotides blocks formation of morphological somites, segment boundaries, and segmented expression of genes normally transcribed in anterior and posterior somites and expression of paraxis implicated in somite epithelialization. Patterning of the anterior PSM is also affected, as judged by the absence of mesp-b, ephrinB2, and ephA4 expression, and the down-regulation of notch5 and notch6. In contrast, the expression of other genes, including mesp-a and papc, in the anterior of somite primordia, and the oscillating expression of deltaC and deltaD in the PSM appear normal. Nevertheless, this expression is apparently insufficient for the maturation of the presumptive somites to proceed to the stage when boundary formation occurs or for the maintenance of anterior/posterior patterning. Mouse embryos that are compound null mutants for Foxc1 and the closely related Foxc2 have no morphological somites and show abnormal expression of Notch signaling pathway genes in the anterior PSM. Therefore, zebrafish foxc1a plays an essential and conserved role in somite formation, regulating both the expression of paraxis and the A/P patterning of somite primordia.

Authors
Topczewska, JM; Topczewski, J; Shostak, A; Kume, T; Solnica-Krezel, L; Hogan, BL
MLA Citation
Topczewska, JM, Topczewski, J, Shostak, A, Kume, T, Solnica-Krezel, L, and Hogan, BL. "The winged helix transcription factor Foxc1a is essential for somitogenesis in zebrafish." Genes Dev 15.18 (September 15, 2001): 2483-2493.
PMID
11562356
Source
pubmed
Published In
Genes & development
Volume
15
Issue
18
Publish Date
2001
Start Page
2483
End Page
2493
DOI
10.1101/gad.907401

The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis.

The murine Foxc1/Mf1 and Foxc2/Mfh1 genes encode closely related forkhead/winged helix transcription factors with overlapping expression in the forming somites and head mesoderm and endothelial and mesenchymal cells of the developing heart and blood vessels. Embryos lacking either Foxc1 or Foxc2, and most compound heterozygotes, die pre- or perinatally with similar abnormal phenotypes, including defects in the axial skeleton and cardiovascular system. However, somites and major blood vessels do form. This suggested that the genes have similar, dose-dependent functions, and compensate for each other in the early development of the heart, blood vessels, and somites. In support of this hypothesis, we show here that compound Foxc1; Foxc2 homozygotes die earlier and with much more severe defects than single homozygotes alone. Significantly, they have profound abnormalities in the first and second branchial arches, and the early remodeling of blood vessels. Moreover, they show a complete absence of segmented paraxial mesoderm, including anterior somites. Analysis of compound homozygotes shows that Foxc1 and Foxc2 are both required for transcription in the anterior presomitic mesoderm of paraxis, Mesp1, Mesp2, Hes5, and Notch1, and for the formation of sharp boundaries of Dll1, Lfng, and ephrinB2 expression. We propose that the two genes interact with the Notch signaling pathway and are required for the prepatterning of anterior and posterior domains in the presumptive somites through a putative Notch/Delta/Mesp regulatory loop.

Authors
Kume, T; Jiang, H; Topczewska, JM; Hogan, BL
MLA Citation
Kume, T, Jiang, H, Topczewska, JM, and Hogan, BL. "The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis." Genes Dev 15.18 (September 15, 2001): 2470-2482.
PMID
11562355
Source
pubmed
Published In
Genes & development
Volume
15
Issue
18
Publish Date
2001
Start Page
2470
End Page
2482
DOI
10.1101/gad.907301

Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm.

Mesodermal signaling is critical for patterning the embryonic endoderm into different tissue domains. Classical tissue transplant experiments in the chick and recent studies in the mouse indicated that interactions with the cardiogenic mesoderm are necessary and sufficient to induce the liver in the ventral foregut endoderm. Using molecular markers and functional assays, we now show that septum transversum mesenchyme cells, a distinct mesoderm cell type, are closely apposed to the ventral endoderm and contribute to hepatic induction. Specifically, using a mouse Bmp4 null mutation and an inhibitor of BMPs, we find that BMP signaling from the septum transversum mesenchyme is necessary to induce liver genes in the endoderm and to exclude a pancreatic fate. BMPs apparently function, in part, by affecting the levels of the GATA4 transcription factor, and work in parallel to FGF signaling from the cardiac mesoderm. BMP signaling also appears critical for morphogenetic growth of the hepatic endoderm into a liver bud. Thus, the endodermal domain for the liver is specified by simultaneous signaling from distinct mesodermal sources.

Authors
Rossi, JM; Dunn, NR; Hogan, BL; Zaret, KS
MLA Citation
Rossi, JM, Dunn, NR, Hogan, BL, and Zaret, KS. "Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm." Genes Dev 15.15 (August 1, 2001): 1998-2009.
PMID
11485993
Source
pubmed
Published In
Genes & development
Volume
15
Issue
15
Publish Date
2001
Start Page
1998
End Page
2009
DOI
10.1101/gad.904601

How does the mouse get its trunk?

Authors
Dunn, NR; Hogan, BL
MLA Citation
Dunn, NR, and Hogan, BL. "How does the mouse get its trunk?." Nat Genet 27.4 (April 2001): 351-352.
PMID
11279507
Source
pubmed
Published In
Nature Genetics
Volume
27
Issue
4
Publish Date
2001
Start Page
351
End Page
352
DOI
10.1038/86829

Sequence and expression of zebrafish foxc1a and foxc1b, encoding conserved forkhead/winged helix transcription factors.

Mouse Foxc1 (previously Mf1) is a member of the conserved forkhead/winged helix transcription factor gene family. It is expressed in many mesodermal tissues including paraxial mesoderm of the trunk and head, prechondrogenic mesenchyme, branchial arches and developing kidney. Homozygous mutants die perinatally with hydrocephalus and skeletal, cardiovascular, ocular and genitourinary defects. Here, we report the cloning and expression of two zebrafish foxc1 homologues, foxc1a and foxc1b. During gastrulation and somitogenesis both genes have similar expression patterns in the hypoblast, paraxial and presomitic mesoderm, somites and trunk adaxial cells. Expression in the somites is downregulated as they differentiate, but is maintained in the sclerotome. Later, some differences in expression pattern emerge. For example, only foxc1a transcripts are detected in the pronephros primodia and in the head mesoderm around the eyes, while only foxc1b is expressed in the pharyngeal arches and pectoral fins. Early expression of foxc1a in the paraxial mesoderm is modified in chordino, swirl, somitabun, and spadetail mutants.

Authors
Topczewska, JM; Topczewski, J; Solnica-Krezel, L; Hogan, BL
MLA Citation
Topczewska, JM, Topczewski, J, Solnica-Krezel, L, and Hogan, BL. "Sequence and expression of zebrafish foxc1a and foxc1b, encoding conserved forkhead/winged helix transcription factors." Mech Dev 100.2 (February 2001): 343-347.
PMID
11165495
Source
pubmed
Published In
Mechanisms of Development
Volume
100
Issue
2
Publish Date
2001
Start Page
343
End Page
347

Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors.

The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualization of the stroma. Previous studies established that the gene encoding heparin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction. We report here the expression during implantation of 21 genes encoding other signaling proteins, including those belonging to the Bone morphogenetic protein (BMP), fibroblast growth factor (FGF), WNT, and Hedgehog (HH) pathways. We find that the attachment reaction is associated with a localized stromal induction of genes encoding BMP-2, FGF-2, and WNT-4. Despite efforts by many investigators, a simple in vitro model of implantation is not yet available to study either the hierarchy of the events triggered in the uterus by the embryo or the function of individual signaling proteins. We have therefore approached these questions by introducing beads loaded with purified factors into the receptive uterus. We show that beads soaked in HB-EGF or insulin-like growth factor-1 (IGF-1), but not other proteins, induce many of the same discrete local responses elicited by the blastocyst, including increased localized vascular permeability, decidualization, and expression of Bmp2 at the sites of the beads. By contrast, the expression domains of Indian hedgehog (Ihh), patched, and noggin become restricted as decidualization proceeds. Significantly, beads containing BMP-2 do not themselves elicit an implantation response but affect the spacing of implantation sites induced by blastocysts cotransferred with the beads.

Authors
Paria, BC; Ma, W; Tan, J; Raja, S; Das, SK; Dey, SK; Hogan, BL
MLA Citation
Paria, BC, Ma, W, Tan, J, Raja, S, Das, SK, Dey, SK, and Hogan, BL. "Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors." Proc Natl Acad Sci U S A 98.3 (January 30, 2001): 1047-1052.
PMID
11158592
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
3
Publish Date
2001
Start Page
1047
End Page
1052
DOI
10.1073/pnas.98.3.1047

Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure.

BACKGROUND: Glaucoma is a blinding disease usually associated with high intraocular pressure (IOP). In some families, abnormal anterior segment development contributes to glaucoma. The genes causing anterior segment dysgenesis and glaucoma in most of these families are not identified and the affected developmental processes are poorly understood. Bone morphogenetic proteins (BMPs) participate in various developmental processes. We tested the importance of Bmp4 gene dosage for ocular development and developmental glaucoma. RESULTS: Bmp4+/- mice have anterior segment abnormalities including malformed, absent or blocked trabecular meshwork and Schlemm's canal drainage structures. Mice with severe drainage structure abnormalities, over 80% or more of their angle's extent, have elevated IOP. The penetrance and severity of abnormalities is strongly influenced by genetic background, being most severe on the C57BL/6J background and absent on some other backgrounds. On the C57BL/6J background there is also persistence of the hyaloid vasculature, diminished numbers of inner retinal cells, and absence of the optic nerve. CONCLUSIONS: We demonstrate that heterozygous deficiency of BMP4 results in anterior segment dysgenesis and elevated IOP. The abnormalities are similar to those in human patients with developmental glaucoma. Thus, BMP4 is a strong candidate to contribute to Axenfeld-Rieger anomaly and other developmental conditions associated with human glaucoma. BMP4 also participates in posterior segment development and wild-type levels are usually critical for optic nerve development on the C57BL/6J background. Bmp4+/- mice are useful for studying various components of ocular development, and may allow identification of strain specific modifiers affecting a variety of ocular phenotypes.

Authors
Chang, B; Smith, RS; Peters, M; Savinova, OV; Hawes, NL; Zabaleta, A; Nusinowitz, S; Martin, JE; Davisson, ML; Cepko, CL; Hogan, BL; John, SW
MLA Citation
Chang, B, Smith, RS, Peters, M, Savinova, OV, Hawes, NL, Zabaleta, A, Nusinowitz, S, Martin, JE, Davisson, ML, Cepko, CL, Hogan, BL, and John, SW. "Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure." BMC Genet 2 (2001): 18-.
PMID
11722794
Source
pubmed
Published In
BMC Genetics
Volume
2
Publish Date
2001
Start Page
18

International Journal of Developmental Biology: Preface

Authors
Hogan, B
MLA Citation
Hogan, B. "International Journal of Developmental Biology: Preface." International Journal of Developmental Biology 45.3 (2001): 455--.
Source
scival
Published In
International Journal of Developmental Biology
Volume
45
Issue
3
Publish Date
2001
Start Page
455-

From embryo to ethics: A career in science and social responsibility

Authors
Hogan, B
MLA Citation
Hogan, B. "From embryo to ethics: A career in science and social responsibility." International Journal of Developmental Biology 45.3 (2001): 477-482.
PMID
11417887
Source
scival
Published In
International Journal of Developmental Biology
Volume
45
Issue
3
Publish Date
2001
Start Page
477
End Page
482

Powerful ideas driven by simple tools: Lessons from experimental embryology

In developmental biology, as in all scientific fields, conceptual advances are tightly coupled to technological innovation. In this review, we trace the evolution of techniques in experimental embryology, from classical ablation to the latest methods utilizing in vivo electroporation, with lens induction as a linking theme.

Authors
Weaver, M; Hogan, B
MLA Citation
Weaver, M, and Hogan, B. "Powerful ideas driven by simple tools: Lessons from experimental embryology." Nature Cell Biology 3.7 (2001): E165-E167.
PMID
11433314
Source
scival
Published In
Nature Cell Biology
Volume
3
Issue
7
Publish Date
2001
Start Page
E165
End Page
E167
DOI
10.1038/35083125

Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle.

Growth and differentiation of postnatal hair follicles are controlled by reciprocal interactions between the dermal papilla and the surrounding epidermal hair precursors. The molecular nature of these interactions is largely unknown, but they are likely to involve several families of signaling molecules, including Fgfs, Wnts and Bmps. To analyze the function of Bmp signaling in postnatal hair development, we have generated transgenic mice expressing the Bmp inhibitor, Noggin, under the control of the proximal Msx2 promoter, which drives expression in proliferating hair matrix cells and differentiating hair precursor cells. Differentiation of the hair shaft but not the inner root sheath is severely impaired in Msx2-Noggin transgenic mice. In addition to hair keratins, the expression of several transcription factors implicated in hair development, including Foxn1 and Hoxc13, is severely reduced in the transgenic hair follicles. Proliferating cells, which are normally restricted to the hair matrix surrounding the dermal papilla, are found in the precortex and hair shaft region. These results identify Bmps as key regulators of the genetic program controlling hair shaft differentiation in postnatal hair follicles.

Authors
Kulessa, H; Turk, G; Hogan, BL
MLA Citation
Kulessa, H, Turk, G, and Hogan, BL. "Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle." EMBO J 19.24 (December 15, 2000): 6664-6674.
PMID
11118201
Source
pubmed
Published In
EMBO Journal
Volume
19
Issue
24
Publish Date
2000
Start Page
6664
End Page
6674
DOI
10.1093/emboj/19.24.6664

Notch/Delta expression in the developing mouse lung.

Factors controlling the differentiation of the multipotent embryonic lung endoderm and mesoderm are poorly understood. Recent evidence that Delta-like 1 (Dll1) and other genes in the Notch/Delta signaling pathway are expressed in the embryonic mouse lung suggests that this pathway is important for cell fate decisions and/or the differentiation of lung cell types. Here, we report the localization of transcripts of several genes encoding members of the Notch/Delta pathway in the early mouse lung. Most genes are expressed in specific populations and so may contribute to cell diversification.

Authors
Post, LC; Ternet, M; Hogan, BL
MLA Citation
Post, LC, Ternet, M, and Hogan, BL. "Notch/Delta expression in the developing mouse lung." Mech Dev 98.1-2 (November 2000): 95-98.
PMID
11044610
Source
pubmed
Published In
Mechanisms of Development
Volume
98
Issue
1-2
Publish Date
2000
Start Page
95
End Page
98

Development and validation of a liquid chromatographic method for the determination of the related substances of ramipril in Altace capsules.

The development and validation of a reversed-phase liquid chromatographic method for the determination of the related substances of 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril) in Altace capsules is described. The method utilizes an ion-pairing agent and a simple two-step gradient for the separation of ramipril and ten related substances from each other in a 40-min run time. Four of the related substances are ramipril diastereomers. To the best of our knowledge, no method described previously in the literature has demonstrated resolution of ramipril from this set of related substances. No method for the determination of the related substances of ramipril is currently described in the United States Pharmacopoeia or the European Pharmacopoeia. The proposed method was validated with respect to accuracy, precision, linearity, and specificity. Also, the method was determined to be robust with regards to the following parameters: mobile phase apparent pH: mobile phase organic content: mobile phase perchlorate concentration; detection wavelength and time dependence of sample and standard stability.

Authors
Hogan, BL; Williams, M; Idiculla, A; Veysoglu, T; Parente, E
MLA Citation
Hogan, BL, Williams, M, Idiculla, A, Veysoglu, T, and Parente, E. "Development and validation of a liquid chromatographic method for the determination of the related substances of ramipril in Altace capsules." J Pharm Biomed Anal 23.4 (September 2000): 637-651.
PMID
10975240
Source
pubmed
Published In
Journal of Pharmaceutical and Biomedical Analysis
Volume
23
Issue
4
Publish Date
2000
Start Page
637
End Page
651

Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis.

Morphogenesis of the mouse lung involves reciprocal interactions between the epithelial endoderm and the surrounding mesenchyme, leading to an invariant early pattern of branching that forms the basis of the respiratory tree. There is evidence that Fibroblast growth factor 10 (Fgf10) and Bone Morphogenetic Protein 4 (Bmp4), expressed in the distal mesenchyme and endoderm, respectively, play important roles in branching morphogenesis. To examine these roles in more detail, we have exploited an in vitro culture system in which isolated endoderm is incubated in Matrigel(TM) substratum with Fgf-loaded beads. In addition, we have used a Bmp4(lacZ) line of mice in which lacZ faithfully reports Bmp4 expression. Analysis of lung endoderm in vivo shows a dynamic pattern of Bmp4(lacZ) expression during bud outgrowth, extension and branching. In vitro, Fgf10 induces both proliferation and chemotaxis of isolated endoderm, whether it is derived from the distal or proximal lung. Moreover, after 48 hours, Bmp4(lacZ) expression is upregulated in the endoderm closest to the bead. Addition of 30-50 ng/ml of exogenous purified Bmp4 to the culture medium inhibits Fgf-induced budding or chemotaxis, and inhibits overall proliferation. By contrast, the Bmp-binding protein Noggin enhances Fgf-induced morphogenesis. Based on these and other results, we propose a model for the combinatorial roles of Fgf10 and Bmp4 in branching morphogenesis of the lung.

Authors
Weaver, M; Dunn, NR; Hogan, BL
MLA Citation
Weaver, M, Dunn, NR, and Hogan, BL. "Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis." Development 127.12 (June 2000): 2695-2704.
PMID
10821767
Source
pubmed
Published In
Development (Cambridge)
Volume
127
Issue
12
Publish Date
2000
Start Page
2695
End Page
2704

Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development.

Anterior segment developmental disorders, including Axenfeld-Rieger anomaly (ARA), variably associate with harmfully elevated intraocular pressure (IOP), which causes glaucoma. Clinically observed dysgenesis does not correlate with IOP, however, and the etiology of glaucoma development is not understood. The forkhead transcription factor genes Foxc1 (formerly Mf1 ) and Foxc2 (formerly Mfh1 ) are expressed in the mesenchyme from which the ocular drainage structures derive. Mutations in the human homolog of Foxc1, FKHL7, cause dominant anterior segment defects and glaucoma in various families. We show that Foxc1 (+/-)mice have anterior segment abnormalities similar to those reported in human patients. These abnormalities include small or absent Schlemm's canal, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils and displaced Schwalbe's line. The penetrance of clinically obvious abnormalities varies with genetic background. In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse. Thus, abnormalities in extracellular matrix synthesis or organization may contribute to development of the ocular phenotypes. Despite the abnormalities in ocular drainage structures in Foxc1 (+/-)mice, IOP was normal in almost all mice analyzed, on all genetic backgrounds and at all ages. Similar abnormalities were found in Foxc2 (+/-)mice, but no disease-associated mutations were identified in the human homolog FKHL14 in 32 ARA patients. Foxc1 (+/-)and Foxc2 (+/-)mice are useful models for studying anterior segment development and its anomalies, and may allow identification of genes that interact with Foxc1 and Foxc2 (or FKHL7 and FKHL14 ) to produce a phenotype with elevated IOP and glaucoma.

Authors
Smith, RS; Zabaleta, A; Kume, T; Savinova, OV; Kidson, SH; Martin, JE; Nishimura, DY; Alward, WL; Hogan, BL; John, SW
MLA Citation
Smith, RS, Zabaleta, A, Kume, T, Savinova, OV, Kidson, SH, Martin, JE, Nishimura, DY, Alward, WL, Hogan, BL, and John, SW. "Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development." Hum Mol Genet 9.7 (April 12, 2000): 1021-1032.
PMID
10767326
Source
pubmed
Published In
Human Molecular Genetics
Volume
9
Issue
7
Publish Date
2000
Start Page
1021
End Page
1032

Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter.

In the normal mouse embryo, Bmp4 is expressed in mesenchymal cells surrounding the Wolffian duct (WD) and ureter stalk, whereas bone morphogenetic protein (BMP) type I receptor genes are transcribed either ubiquitously (Alk3) or exclusively in the WD and ureter epithelium (Alk6). Bmp4 heterozygous null mutant mice display, with high penetrance, abnormalities that mimic human congenital anomalies of the kidney and urinary tract (CAKUT), including hypo/dysplastic kidneys, hydroureter, ectopic ureterovesical (UV) junction, and double collecting system. Analysis of mutant embryos suggests that the kidney hypo/dysplasia results from reduced branching of the ureter, whereas the ectopic UV junction and double collecting system are due to ectopic ureteral budding from the WD and accessory budding from the main ureter, respectively. In the cultured metanephros deprived of sulfated glycosaminoglycans (S-GAGs), BMP4-loaded beads partially rescue growth and elongation of the ureter. By contrast, when S-GAGs synthesis is not inhibited, BMP4 beads inhibit ureter branching and expression of Wnt 11, a target of glial cell-derived neurotrophic factor signaling. Thus, Bmp4 has 2 functions in the early morphogenesis of the kidney and urinary tract. One is to inhibit ectopic budding from the WD or the ureter stalk by antagonizing inductive signals from the metanephric mesenchyme to the illegitimate sites on the WD. The other is to promote the elongation of the branching ureter within the metanephros, thereby promoting kidney morphogenesis.

Authors
Miyazaki, Y; Oshima, K; Fogo, A; Hogan, BL; Ichikawa, I
MLA Citation
Miyazaki, Y, Oshima, K, Fogo, A, Hogan, BL, and Ichikawa, I. "Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter." J Clin Invest 105.7 (April 2000): 863-873.
PMID
10749566
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
105
Issue
7
Publish Date
2000
Start Page
863
End Page
873
DOI
10.1172/JCI8256

Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract.

The murine genes, Foxc1 and Foxc2 (previously, Mf1 and Mfh1), encode forkhead/winged helix transcription factors with virtually identical DNA-binding domains and overlapping expression patterns in various embryonic tissues. Foxc1/Mf1 is disrupted in the mutant, congenital hydrocephalus (Foxc1/Mf1(ch)), which has multiple developmental defects. We show here that, depending on the genetic background, most Foxc1 homozygous mutants are born with abnormalities of the metanephric kidney, including duplex kidneys and double ureters, one of which is a hydroureter. Analysis of embryos reveals that Foxc1 homozygotes have ectopic mesonephric tubules and ectopic anterior ureteric buds. Moreover, expression in the intermediate mesoderm of Glial cell-derived neurotrophic factor (Gdnf), a primary inducer of the ureteric bud, is expanded more anteriorly in Foxc1 homozygous mutants compared with wild type. These findings support the hypothesis of Mackie and Stephens concerning the etiology of duplex kidney and hydroureter in human infants with congenital kidney abnormalities (Mackie, G. G. and Stephens, F. G. (1975) J. Urol. 114, 274-280). Previous studies established that most Foxc1(lacZ )Foxc2(tm1) compound heterozygotes have the same spectrum of cardiovascular defects as single homozygous null mutants, demonstrating interaction between the two genes in the cardiovascular system. Here, we show that most compound heterozygotes have hypoplastic kidneys and a single hydroureter, while all heterozygotes are normal. This provides evidence that the two genes interact in kidney as well as heart development.

Authors
Kume, T; Deng, K; Hogan, BL
MLA Citation
Kume, T, Deng, K, and Hogan, BL. "Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract." Development 127.7 (April 2000): 1387-1395.
PMID
10704385
Source
pubmed
Published In
Development (Cambridge)
Volume
127
Issue
7
Publish Date
2000
Start Page
1387
End Page
1395

Out of Eden: stem cells and their niches.

Stem cells are currently in the news for two reasons: the successful cultivation of human embryonic stem cell lines and reports that adult stem cells can differentiate into developmentally unrelated cell types, such as nerve cells into blood cells. Both intrinsic and extrinsic signals regulate stem cell fate and some of these signals have now been identified. Certain aspects of the stem cell microenvironment, or niche, are conserved between tissues, and this can be exploited in the application of stem cells to tissue replacement therapy.

Authors
Watt, FM; Hogan, BL
MLA Citation
Watt, FM, and Hogan, BL. "Out of Eden: stem cells and their niches." Science 287.5457 (February 25, 2000): 1427-1430. (Review)
PMID
10688781
Source
pubmed
Published In
Science
Volume
287
Issue
5457
Publish Date
2000
Start Page
1427
End Page
1430

Retina- and ventral forebrain-specific Cre recombinase activity in transgenic mice

Authors
Furuta, Y; Lagutin, O; Hogan, BLM; Oliver, GC
MLA Citation
Furuta, Y, Lagutin, O, Hogan, BLM, and Oliver, GC. "Retina- and ventral forebrain-specific Cre recombinase activity in transgenic mice." Genesis 26.2 (February 1, 2000): 130-132.
Source
scopus
Published In
Genesis: the Journal of Genetics and Development
Volume
26
Issue
2
Publish Date
2000
Start Page
130
End Page
132
DOI
10.1002/(SICI)1526-968X(200002)26:2<130::AID-GENE9>3.0.CO;2-I

Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged helix gene, Mf2.

Mf2 (mesoderm/mesenchyme forkhead 2) encodes a forkhead/winged helix transcription factor expressed in numerous tissues of the mouse embryo, including paraxial mesoderm, somites, branchial arches, vibrissae, developing central nervous system, and developing kidney. We have generated mice homozygous for a null mutation in the Mf2 gene (Mf2(lacZ)) to examine its role during embryonic development. The lacZ allele also allows monitoring of Mf2 gene expression. Homozygous null mutants are viable and fertile and have no major developmental defects. Some mutants show renal abnormalities, including kidney hypoplasia and hydroureter, but the penetrance of this phenotype is only 40% or lower, depending on the genetic background. These data suggest that Mf2 can play a unique role in kidney development, but there is functional redundancy in this organ and other tissues with other forkhead/winged helix genes.

Authors
Kume, T; Deng, K; Hogan, BL
MLA Citation
Kume, T, Deng, K, and Hogan, BL. "Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged helix gene, Mf2." Mol Cell Biol 20.4 (February 2000): 1419-1425.
PMID
10648626
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
20
Issue
4
Publish Date
2000
Start Page
1419
End Page
1425

Retina- and ventral forebrain-specific Cre recombinase activity in transgenic mice.

Authors
Furuta, Y; Lagutin, O; Hogan, BL; Oliver, GC
MLA Citation
Furuta, Y, Lagutin, O, Hogan, BL, and Oliver, GC. "Retina- and ventral forebrain-specific Cre recombinase activity in transgenic mice." Genesis 26.2 (February 2000): 130-132.
PMID
10686607
Source
pubmed
Published In
Genesis: the Journal of Genetics and Development
Volume
26
Issue
2
Publish Date
2000
Start Page
130
End Page
132

Bone morphogenetic protein-6 is a marker of serous acinar cell differentiation in normal and neoplastic human salivary gland.

Bone morphogenetic protein (BMP-6, also known as vegetal-pale-gene-related and decaplentaplegic-vegetal-related) is a member of the transforming growth factor-beta superfamily of multifunctional signaling molecules. BMP-6 appears to play various biological roles in developing tissues, including regulation of epithelial differentiation. To study the possible involvement of BMP-6 in normal and neoplastic human salivary glands, we compared its mRNA and protein expression in 4 fetal and 15 adult salivary glands and in 22 benign and 32 malignant salivary gland tumors. In situ hybridization and Northern blot analysis indicated that BMP-6 transcripts are expressed at low levels in acinar cells of adult submandibular glands but not in ductal or stromal cells. BMP-6 was immunolocated specifically in serous acini of parotid and submandibular glands. None was found in primitive fetal acini or any other types of cell in adult salivary glands, including mucous acini and epithelial cells of intercalated, striated, and excretory ducts. All 16 cases of acinic cell carcinoma consistently exhibited cytoplasmic BMP-6 staining in the acinar tumor cells. Other cell types in these tumors, including intercalated duct-like cells, clear, vacuolated cells, and nonspecific glandular cells, exhibited no cytoplasmic BMP-6 staining. Other benign and malignant salivary gland tumors lacked BMP-6 immunoreactivity, except in areas of squamous differentiation. The results indicate that in salivary glands, BMP-6 expression is uniquely associated with acinar cell differentiation and suggest that BMP-6 may play a role in salivary gland function. More importantly, our experience of differential diagnostic problems related to salivary gland tumors suggests that the demonstration of consistent and specific BMP-6 immunoreactivity in acinic cell carcinoma is likely to be of clinical value.

Authors
Heikinheimo, KA; Laine, MA; Ritvos, OV; Voutilainen, RJ; Hogan, BL; Leivo, IV
MLA Citation
Heikinheimo, KA, Laine, MA, Ritvos, OV, Voutilainen, RJ, Hogan, BL, and Leivo, IV. "Bone morphogenetic protein-6 is a marker of serous acinar cell differentiation in normal and neoplastic human salivary gland." Cancer Res 59.22 (November 15, 1999): 5815-5821.
PMID
10582704
Source
pubmed
Published In
Cancer Research
Volume
59
Issue
22
Publish Date
1999
Start Page
5815
End Page
5821

Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles.

The murine Mf1 and Mfh1 genes have overlapping patterns of expression in the embryo and encode forkhead/winged helix transcription factors with virtually identical DNA binding domains. Previous studies have shown that Mfh1 null mutants have severe cardiovascular defects, including interruptions and coarctations of the aortic arch and ventricular septal defects (Iida et al., Development 124, 4627-4638, 1997). Here, we show that Mf1(lacZ) homozygous null mutants also have a similar spectrum of cardiovascular abnormalities. Moreover, most embryos doubly heterozygous for Mfh1(tm1) and Mf1(lacZ) die before birth with interruptions and coarctations of the aortic arch, dysgenesis of the aortic and pulmonary valves, ventricular septal defects, and other cardiac anomalies. This nonallelic noncomplementation and the similar patterns of expression of the two genes in the mesenchyme and endothelial cells of the branchial arches, outflow tract, and heart suggest that Mf1 and Mfh1 play interactive roles in the morphogenesis of the cardiovascular system. Implications for the development of human congenital heart defects are discussed.

Authors
Winnier, GE; Kume, T; Deng, K; Rogers, R; Bundy, J; Raines, C; Walter, MA; Hogan, BL; Conway, SJ
MLA Citation
Winnier, GE, Kume, T, Deng, K, Rogers, R, Bundy, J, Raines, C, Walter, MA, Hogan, BL, and Conway, SJ. "Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles." Dev Biol 213.2 (September 15, 1999): 418-431.
PMID
10479458
Source
pubmed
Published In
Developmental Biology
Volume
213
Issue
2
Publish Date
1999
Start Page
418
End Page
431
DOI
10.1006/dbio.1999.9382

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693-1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

Authors
Weaver, M; Yingling, JM; Dunn, NR; Bellusci, S; Hogan, BL
MLA Citation
Weaver, M, Yingling, JM, Dunn, NR, Bellusci, S, and Hogan, BL. "Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development." Development 126.18 (September 1999): 4005-4015.
PMID
10457010
Source
pubmed
Published In
Development (Cambridge)
Volume
126
Issue
18
Publish Date
1999
Start Page
4005
End Page
4015

Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin.

Expression of the cytokine osteopontin (OPN) is elevated in granulomas caused by Mycobacterium tuberculosis. We tested the hypothesis that OPN contributes to host protection in a mouse model of mycobacterial infection. When infected with Mycobacterium bovis BCG, mice lacking a functional OPN gene had more severe infections characterized by heavier bacterial loads and a delayed clearance of the bacteria. The OPN-null mice had greater granuloma burdens consistent with the elevated bacterial load. The ability of osteopontin to facilitate the clearance of mycobacteria was most pronounced early after infection and appeared to be independent of known mediators of resistance to infection by mycobacteria: antigen-specific T-cell immunity, gamma interferon production, and nitric oxide production. BCG grew more rapidly in macrophages derived from OPN-null mice than in those from wild-type mice, demonstrating that the null phenotype was due to an intrinsic macrophage defect. These results indicate that osteopontin augments the host response against a mycobacterial infection and that it acts independently from other antimycobacterial resistance mechanisms.

Authors
Nau, GJ; Liaw, L; Chupp, GL; Berman, JS; Hogan, BL; Young, RA
MLA Citation
Nau, GJ, Liaw, L, Chupp, GL, Berman, JS, Hogan, BL, and Young, RA. "Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin." Infect Immun 67.8 (August 1999): 4223-4230.
PMID
10417195
Source
pubmed
Published In
Infection and immunity
Volume
67
Issue
8
Publish Date
1999
Start Page
4223
End Page
4230

The forkhead/winged-helix gene, Mf1, is necessary for the normal development of the cornea and formation of the anterior chamber in the mouse eye.

Mf1, which encodes a winged-helix/forkhead transcription factor, is the murine homolog of human FKHL7, mutated in individuals with autosomal dominant inherited dysgenesis of the anterior segment of the eye (Axenfeld-Reiger anomaly). Mouse embryos homozygous for null mutations in Mf1 (Mf1(lacZ) and Mf1(ch)) show severely abnormal development of the anterior segment. The cornea fails to separate from the lens, resulting in the complete absence of an anterior chamber. There is no differentiation of the inner corneal endothelial layer, as judged by electron microscopy and by absence of labeling with monoclonal antibody to zonula occludens protein 1, a normal component of occluding junctions in wild-type endothelial cells. In addition, the mutant corneal stroma is disorganized and the epithelium thicker than normal. The Mf1 gene is normally expressed in the periocular mesenchyme at E11.5 but is downregulated as the corneal endothelium differentiates. In contrast, Mf1(lacZ) expression persists longer in mutant corneal mesenchyme, and abnormal expression is also seen in the mutant corneal epithelium. Based on classical studies with the chick embryonic eye, a model is proposed for the differentiation of the mammalian corneal endothelium from mesenchyme in response to putative signals from the lens. Possible roles for Mf1 in this process are discussed.

Authors
Kidson, SH; Kume, T; Deng, K; Winfrey, V; Hogan, BL
MLA Citation
Kidson, SH, Kume, T, Deng, K, Winfrey, V, and Hogan, BL. "The forkhead/winged-helix gene, Mf1, is necessary for the normal development of the cornea and formation of the anterior chamber in the mouse eye." Dev Biol 211.2 (July 15, 1999): 306-322.
PMID
10395790
Source
pubmed
Published In
Developmental Biology
Volume
211
Issue
2
Publish Date
1999
Start Page
306
End Page
322
DOI
10.1006/dbio.1999.9314

The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart.

Mammalian Tolloid-like 1 (mTLL-1) is an astacin-like metalloprotease, highly similar in domain structure to the morphogenetically important proteases bone morphogenetic protein-1 (BMP-1) and Drosophila Tolloid. To investigate possible roles for mTLL-1 in mammalian development, we have used gene targeting in ES cells to produce mice with a disrupted allele for the corresponding gene, Tll1. Homozygous mutants were embryonic lethal, with death at mid-gestation from cardiac failure and a unique constellation of developmental defects that were apparently confined solely to the heart. Constant features were incomplete formation of the muscular interventricular septum and an abnormal and novel positioning of the heart and aorta. Consistent with roles in cardiac development, Tll1 expression was specific to precardiac tissue and endocardium in 7.5 and 8.5 days p.c. embryos, respectively. Tll1 expression was also high in the developing interventricular septum, where expression of the BMP-1 gene, Bmp1, was not observed. Cardiac structures that were not affected in Tll1-/- embryos either showed no Tll1 expression (atrio-ventricular cushions) or showed overlapping expression of Tll1 and Bmp1 (aortico-pulmonary septum), suggesting that products of the Bmp1 gene may be capable of functionally substituting for mTLL-1 at sites in which they are co-expressed. Together, the various data show that mTLL-1 plays multiple roles in formation of the mammalian heart and is essential for formation of the interventricular septum.

Authors
Clark, TG; Conway, SJ; Scott, IC; Labosky, PA; Winnier, G; Bundy, J; Hogan, BL; Greenspan, DS
MLA Citation
Clark, TG, Conway, SJ, Scott, IC, Labosky, PA, Winnier, G, Bundy, J, Hogan, BL, and Greenspan, DS. "The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart." Development 126.12 (June 1999): 2631-2642.
PMID
10331975
Source
pubmed
Published In
Development (Cambridge)
Volume
126
Issue
12
Publish Date
1999
Start Page
2631
End Page
2642

Bmp4 is required for the generation of primordial germ cells in the mouse embryo.

In many organisms the allocation of primordial germ cells (PGCs) is determined by the inheritance of maternal factors deposited in the egg. However, in mammals, inductive cell interactions are required around gastrulation to establish the germ line. Here, we show that Bmp4 homozygous null embryos contain no PGCs. They also lack an allantois, an extraembryonic mesodermal tissue derived, like the PGCs, from precursors in the proximal epiblast. Heterozygotes have fewer PGCs than normal, due to a reduction in the size of the founding population and not to an effect on its subsequent expansion. Analysis of beta-galactosidase activity in Bmp4(lacZneo) embryos reveals that prior to gastrulation, Bmp4 is expressed in the extraembryonic ectoderm. Later, Bmp4 is expressed in the extraembryonic mesoderm, but not in PGCs. Chimera analysis indicates that it is the Bmp4 expression in the extraembryonic ectoderm that regulates the formation of allantois and primordial germ cell precursors, and the size of the founding population of PGCs. The initiation of the germ line in the mouse therefore depends on a secreted signal from the previously segregated, extraembryonic, trophectoderm lineage.

Authors
Lawson, KA; Dunn, NR; Roelen, BA; Zeinstra, LM; Davis, AM; Wright, CV; Korving, JP; Hogan, BL
MLA Citation
Lawson, KA, Dunn, NR, Roelen, BA, Zeinstra, LM, Davis, AM, Wright, CV, Korving, JP, and Hogan, BL. "Bmp4 is required for the generation of primordial germ cells in the mouse embryo." Genes Dev 13.4 (February 15, 1999): 424-436.
PMID
10049358
Source
pubmed
Published In
Genes & development
Volume
13
Issue
4
Publish Date
1999
Start Page
424
End Page
436

Morphogenesis.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Morphogenesis." Cell 96.2 (January 22, 1999): 225-233. (Review)
PMID
9988217
Source
pubmed
Published In
Cell
Volume
96
Issue
2
Publish Date
1999
Start Page
225
End Page
233

Mouse primordial germ cells. Isolation and in vitro culture.

Authors
Labosky, PA; Hogan, BL
MLA Citation
Labosky, PA, and Hogan, BL. "Mouse primordial germ cells. Isolation and in vitro culture." Methods Mol Biol 97 (1999): 201-212. (Review)
PMID
10443366
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
97
Publish Date
1999
Start Page
201
End Page
212
DOI
10.1385/1-59259-270-8:201

Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin

Expression of the cytokine osteopontin (OPN) is elevated in granulomas caused by Mycobacterium tuberculosis. We tested the hypothesis that OPN contributes to host protection in a mouse model of mycobacterial infection. When infected with M. bovis BCG, mice lacking a functional OPN gene had more severe infections characterized by heavier bacterial loads and a delayed clearance of the bacteria. The OPN-null mice had greater granuloma burdens consistent with the elevated bacterial load. The ability of osteopontin to facilitate the clearance of mycobacteria was most pronounced early after infection and appeared to be independent of known mediators of resistance to infection by mycobacteria: antigen-specific T-cell immunity, gamma-interferon production, and nitric oxide production. BCG grew more rapidly in macrophages derived from OPN-null mice than in those from wild-type mice, demonstrating that the null phenotype was due to an intrinsic macrophage defect. These results indicate that osteopontin augments the host response against a mycobacterial infection and that it acts independently from other antimycobacterial resistance mechanisms.

Authors
Nau, GJ; Liaw, L; Chupp, GL; Berman, JS; Hogan, BLM; Young, RA
MLA Citation
Nau, GJ, Liaw, L, Chupp, GL, Berman, JS, Hogan, BLM, and Young, RA. "Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin." International Journal of Leprosy and Other Mycobacterial Diseases 67.4 SUPPL. (1999): 507-508.
Source
scival
Published In
International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association
Volume
67
Issue
4 SUPPL.
Publish Date
1999
Start Page
507
End Page
508

Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men

Angiotensin type 2 receptor gene null mutant mice display congenital anomalies of the kidney and urinary tract (CAKUT). Various features of mouse CAKUT impressively mimic human CAKUT. Studies of the human type 2 receptor (AGTR2) gene in two independent cohorts found that a significant association exists between CAKUT and a nucleotide transition within the lariat branchpoint motif of intron 1, which perturbs AGTR2 mRNA splicing efficiency. AGTR2, therefore, has a significant ontogenic role for the kidney and urinary tract system. Studies revealed that the establishment of CAKUT is preceded by delayed apoptosis of undifferentiated mesenchymal cells surrounding the urinary tract during key ontogenic events, from the ureteral budding to the expansive growth of the kidney and ureter.

Authors
Nishimura, H; Yerkes, E; Hohenfellner, K; Miyazaki, Y; Ma, J; Hunley, TE; Yoshida, H; Ichiki, T; Threadgill, D; III, JAP; Hogan, BML; Fogo, A; III, JWB; Inagami, T; Ichikawa, I
MLA Citation
Nishimura, H, Yerkes, E, Hohenfellner, K, Miyazaki, Y, Ma, J, Hunley, TE, Yoshida, H, Ichiki, T, Threadgill, D, III, JAP, Hogan, BML, Fogo, A, III, JWB, Inagami, T, and Ichikawa, I. "Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men." Molecular Cell 3.1 (1999): 1-10.
PMID
10024874
Source
scival
Published In
Molecular Cell
Volume
3
Issue
1
Publish Date
1999
Start Page
1
End Page
10
DOI
10.1016/S1097-2765(00)80169-0

BMP4 is essential for lens induction in the mouse embryo.

Vertebrate lens development is a classical model system for studying embryonic tissue interactions. Little is known, however, about the molecules mediating such inductive events. Here, we show that Bmp4, which is expressed strongly in the optic vesicle and weakly in the surrounding mesenchyme and surface ectoderm, has crucial roles during lens induction. In Bmp4(tm1) homozygous null mutant embryos, lens induction is absent, but the process can be rescued by exogenous BMP4 protein applied into the optic vesicle in explant cultures. This is associated with rescue of ectodermal expression of Sox2, an early lens placode marker. Substituting the optic vesicle in explant cultures with BMP4-carrying beads, however, does not lead to lens induction, indicating that other factors produced by the optic vesicle are involved. BMP4 appears to regulate expression of a putative downstream gene, Msx2, in the optic vesicle. No change in Pax6 expression is seen in Bmp4(tm1) mutant eyes, and Bmp4 expression appears unaffected in the eyes of homozygous Pax6(Sey-1Neu), suggesting that PAX6 and BMP4 function independently. Based on these results we propose that BMP4 is required for the optic vesicle to manifest its lens-inducing activity, by regulating downstream genes and/or serving as one component of multiple inductive signals.

Authors
Furuta, Y; Hogan, BL
MLA Citation
Furuta, Y, and Hogan, BL. "BMP4 is essential for lens induction in the mouse embryo." Genes Dev 12.23 (December 1, 1998): 3764-3775.
PMID
9851982
Source
pubmed
Published In
Genes & development
Volume
12
Issue
23
Publish Date
1998
Start Page
3764
End Page
3775

A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is expressed during early embryogenesis.

The transcription factor FAST-1 has recently been shown to play a key role in the specification of mesoderm by TGF beta superfamily signals in the early Xenopus embryo. We have cloned Fast1, a mouse homologue of Xenopus FAST-1, and characterized its expression during embryogenesis and function in activin/TGF beta signal transduction. In vitro, Fast1 associates with Smads in response to an activin/TGF beta signal to form a complex that recognizes the Xenopus activin responsive element (ARE) targeted by Xenopus FAST-1. In intact cells, introduction of Fast1 confers activin/TGF beta regulation of an ARE-luciferase reporter. In embryos, Fast1 is expressed predominantly throughout the epiblast before gastrulation and declines as development progresses. We propose that mouse Fast1, like Xenopus FAST-1, mediates TGF beta superfamily signals specifying developmental fate during early embryogenesis.

Authors
Weisberg, E; Winnier, GE; Chen, X; Farnsworth, CL; Hogan, BL; Whitman, M
MLA Citation
Weisberg, E, Winnier, GE, Chen, X, Farnsworth, CL, Hogan, BL, and Whitman, M. "A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is expressed during early embryogenesis." Mech Dev 79.1-2 (December 1998): 17-27.
PMID
10349617
Source
pubmed
Published In
Mechanisms of Development
Volume
79
Issue
1-2
Publish Date
1998
Start Page
17
End Page
27

Formation of Rathke's pouch requires dual induction from the diencephalon.

Targeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, Titf1) in mice results in ablation of the pituitary. Paradoxically, while T/ebp is expressed in the ventral diencephalon during forebrain formation, it is not expressed in Rathke's pouch or in the pituitary gland at any time of embryogenesis. Examination of pituitary development in the T/ebp homozygous null mutant embryos revealed that a pouch rudiment is initially formed but is eliminated by programmed cell death before formation of a definitive pouch. In the diencephalon of the mutant, Bmp4 expression is maintained, whereas Fgf8 expression is not detectable. These data and additional genetic and molecular observations suggest that Rathke's pouch develops in a two-step process that requires at least two sequential inductive signals from the diencephalon. First, BMP4 is required for induction and formation of the pouch rudiment, a role confirmed by analysis of Bmp4 homozygous null mutant embryos. Second, FGF8 is necessary for activation of the key regulatory gene Lhx3 and subsequent development of the pouch rudiment into a definitive pouch. This study provides firm molecular genetic evidence that morphogenesis of the pituitary primordium is induced in vivo by signals from the adjacent diencephalon.

Authors
Takuma, N; Sheng, HZ; Furuta, Y; Ward, JM; Sharma, K; Hogan, BL; Pfaff, SL; Westphal, H; Kimura, S; Mahon, KA
MLA Citation
Takuma, N, Sheng, HZ, Furuta, Y, Ward, JM, Sharma, K, Hogan, BL, Pfaff, SL, Westphal, H, Kimura, S, and Mahon, KA. "Formation of Rathke's pouch requires dual induction from the diencephalon." Development 125.23 (December 1998): 4835-4840.
PMID
9806931
Source
pubmed
Published In
Development (Cambridge)
Volume
125
Issue
23
Publish Date
1998
Start Page
4835
End Page
4840

Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly.

Genetic linkage, genome mismatch scanning, and analysis of patients with alterations of chromosome 6 have indicated that a major locus for development of the anterior segment of the eye, IRID1, is located at 6p25. Abnormalities of this locus lead to glaucoma. FKHL7 (also called "FREAC3"), a member of the forkhead/winged-helix transcription-factor family, has also been mapped to 6p25. DNA sequencing of FKHL7 in five IRID1 families and 16 sporadic patients with anterior-segment defects revealed three mutations: a 10-bp deletion predicted to cause a frameshift and premature protein truncation prior to the FKHL7 forkhead DNA-binding domain, as well as two missense mutations of conserved amino acids within the FKHL7 forkhead domain. Mf1, the murine homologue of FKHL7, is expressed in the developing brain, skeletal system, and eye, consistent with FKHL7 having a role in ocular development. However, mutational screening and genetic-linkage analyses excluded FKHL7 from underlying the anterior-segment disorders in two IRID1 families with linkage to 6p25. Our findings demonstrate that, although mutations of FKHL7 result in anterior-segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is also located at 6p25.

Authors
Mears, AJ; Jordan, T; Mirzayans, F; Dubois, S; Kume, T; Parlee, M; Ritch, R; Koop, B; Kuo, WL; Collins, C; Marshall, J; Gould, DB; Pearce, W; Carlsson, P; Enerbäck, S; Morissette, J; Bhattacharya, S; Hogan, B; Raymond, V; Walter, MA
MLA Citation
Mears, AJ, Jordan, T, Mirzayans, F, Dubois, S, Kume, T, Parlee, M, Ritch, R, Koop, B, Kuo, WL, Collins, C, Marshall, J, Gould, DB, Pearce, W, Carlsson, P, Enerbäck, S, Morissette, J, Bhattacharya, S, Hogan, B, Raymond, V, and Walter, MA. "Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly." Am J Hum Genet 63.5 (November 1998): 1316-1328.
PMID
9792859
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
63
Issue
5
Publish Date
1998
Start Page
1316
End Page
1328
DOI
10.1086/302109

Angiotensin induces the urinary peristaltic machinery during the perinatal period.

The embryonic development of mammalian kidneys is completed during the perinatal period with a dramatic increase in urine production, as the burden of eliminating nitrogenous metabolic waste shifts from the placenta to the kidney. This urine is normally removed by peristaltic contraction of the renal pelvis, a smooth muscle structure unique to placental mammals. Mutant mice completely lacking angiotensin type 1 receptor genes do not develop a renal pelvis, resulting in the buildup of urine and progressive kidney damage. In mutants the ureteral smooth muscle layer is hypoplastic and lacks peristaltic movements. We show that angiotensin can induce the ureteral smooth muscles in organ cultures of wild-type, but not mutant, ureteral tissues and that, in wild-type mice, expression of both renal angiotensin and the receptor are transiently upregulated at the renal outlet at birth. These results reveal a new role for angiotensin in the unique cellular adaptations of the mammalian kidney to the physiological stresses of postnatal life.

Authors
Miyazaki, Y; Tsuchida, S; Nishimura, H; Pope, JC; Harris, RC; McKanna, JM; Inagami, T; Hogan, BL; Fogo, A; Ichikawa, I
MLA Citation
Miyazaki, Y, Tsuchida, S, Nishimura, H, Pope, JC, Harris, RC, McKanna, JM, Inagami, T, Hogan, BL, Fogo, A, and Ichikawa, I. "Angiotensin induces the urinary peristaltic machinery during the perinatal period." J Clin Invest 102.8 (October 15, 1998): 1489-1497.
PMID
9788961
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
102
Issue
8
Publish Date
1998
Start Page
1489
End Page
1497
DOI
10.1172/JCI4401

Epithelial/mesenchymal interactions and branching morphogenesis of the lung.

The establishment of branched tubular epithelial structures is critical for the viability of multicellular organisms: the tracheal system in Drosophila and the vertebrate lung being two such structures. Although there are obvious differences in the complexity of these branched organs, many of the underlying mechanisms and genes regulating their development appear to have been evolutionarily conserved.

Authors
Hogan, BL; Yingling, JM
MLA Citation
Hogan, BL, and Yingling, JM. "Epithelial/mesenchymal interactions and branching morphogenesis of the lung." Curr Opin Genet Dev 8.4 (August 1998): 481-486. (Review)
PMID
9729726
Source
pubmed
Published In
Current Opinion in Genetics & Development
Volume
8
Issue
4
Publish Date
1998
Start Page
481
End Page
486

Mice lacking Bmp6 function

Bmp6, a member of the 60A sub-group of bone morphogenetic proteins (BMPs), is expressed in diverse sites in the developing mouse embryo from preimplanitation stages onwards. To evaluate roles for Bmp6 signaling in vivo, gene targeting was used to generate a null mutation at the Bmp6 locus. The resulting Bmp6 mutant mice are viable and fertile, and show no overt defects in tissues known to express Bmp6 mRNA. The skeletal elements of newborn and adult mutants are indistinguishable from wild-type. However, careful examination of skeletogenesis in late gestation embryos reveals a consistent delay in ossification strictly confined to the developing sternum. In situ hybridization studies in the developing long bones and sternum show thai other BMP family members are expressed in overlapping domains. In particular we find that Bmp2 and Bmp6 are coexpressed in hypertrophic cartilage, suggesting that Bmp2 may functionally compensate in Bmp6 null mice. The defects in sternum development in Bmp6 null mice are likely to be associated with a transient early expression of Bmp6 in the sternal bands, prior to ossification. These sternal defects are slightly exacerbated in Bmp5/6 double mutant animals.

Authors
Solloway, MJ; Dudley, AT; Bikoff, EK; Lyons, KM; Hogan, BLM; Robertson, EJ
MLA Citation
Solloway, MJ, Dudley, AT, Bikoff, EK, Lyons, KM, Hogan, BLM, and Robertson, EJ. "Mice lacking Bmp6 function." Developmental Genetics 22.4 (July 15, 1998): 321-339.
Source
scopus
Published In
Developmental Genetics
Volume
22
Issue
4
Publish Date
1998
Start Page
321
End Page
339
DOI
10.1002/(SICI)1520-6408(1998)22:4<321::AID-DVG3>3.0.CO;2-8

Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice

Analysis of the skeletal phenotypes caused by the genetic inactivation of individual Bmps, along with the study of their expression patterns, suggest possible functional redundancy of these molecules. To investigate the effect on skeleton development of the combined absence of some Bmp genes expressed in the same areas, we have intercrossed heterozygous Bmp7 mice with Bmp2(+/), Bmp4(+/-), or Bmp5(+/-) animals. Bmp2/7 and Bmp5/7 double heterozygous animals do not present with any abnormalities. In contrast, Bmp4/7 double heterozygotes develop minor defects in two restricted areas of the skeleton, the rib cage, and the distal part of the limbs. In the ribs, Bmp4 and Bmp7 seem to act in the same pathway to assure proper guidance of mesenchymal condensations of the ribs extending toword the sternum. In the limbs, these molecules appear to play a similar role in controlling digit number, possibly through induction of apoptosis in the interdigital and anterior mesenchyme.

Authors
Katagiri, T; Boorla, S; Frendo, JL; Hogan, BLM; Karsenty, G
MLA Citation
Katagiri, T, Boorla, S, Frendo, JL, Hogan, BLM, and Karsenty, G. "Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice." Developmental Genetics 22.4 (July 15, 1998): 340-348.
Source
scopus
Published In
Developmental Genetics
Volume
22
Issue
4
Publish Date
1998
Start Page
340
End Page
348
DOI
10.1002/(SICI)1520-6408(1998)22:4<340::AID-DVG4>3.0.CO;2-6

The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus.

Mf1 encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocular mesenchyme, meninges, endothelial cells, and kidney. Homozygous null Mf1lacZ mice die at birth with hydrocephalus, eye defects, and multiple skeletal abnormalities identical to those of the classical mutant, congenital hydrocephalus. We show that congenital hydrocephalus involves a point mutation in Mf1, generating a truncated protein lacking the DNA-binding domain. Mesenchyme cells from Mf1lacZ embryos differentiate poorly into cartilage in micromass culture and do not respond to added BMP2 and TGFbeta1. The differentiation of arachnoid cells in the mutant meninges is also abnormal. The human Mf1 homolog FREAC3 is a candidate gene for ocular dysgenesis and glaucoma mapping to chromosome 6p25-pter, and deletions of this region are associated with multiple developmental disorders, including hydrocephaly and eye defects.

Authors
Kume, T; Deng, KY; Winfrey, V; Gould, DB; Walter, MA; Hogan, BL
MLA Citation
Kume, T, Deng, KY, Winfrey, V, Gould, DB, Walter, MA, and Hogan, BL. "The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus." Cell 93.6 (June 12, 1998): 985-996.
PMID
9635428
Source
pubmed
Published In
Cell
Volume
93
Issue
6
Publish Date
1998
Start Page
985
End Page
996

Altered wound healing in mice lacking a functional osteopontin gene (spp1).

Osteopontin (OPN) is an arginine-glycine-aspartate (RGD)- containing glycoprotein encoded by the gene secreted phosphoprotein 1 (spp1). spp1 is expressed during embryogenesis, wound healing, and tumorigenesis; however, its in vivo functions are not well understood. Therefore, OPN null mutant mice were generated by targeted mutagenesis in embryonic stem cells. In OPN mutant mice, embryogenesis occurred normally, and mice were fertile. Since OPN shares receptors with vitronectin (VN), we tested for compensation by creating mice lacking both OPN and VN. The double mutants were also viable, suggesting that other RGD-containing ligands replace the embryonic loss of both proteins. We tested the healing of OPN mutants after skin incisions, where spp1 was upregulated as early as 6 h after wounding. Although the tensile properties of the wounds were unchanged, ultrastructural analysis showed a significantly decreased level of debridement, greater disorganization of matrix, and an alteration of collagen fibrillogenesis leading to small diameter collagen fibrils in the OPN mutant mice. These data indicate a role for OPN in tissue remodeling in vivo, and suggest physiological functions during matrix reorganization after injury.

Authors
Liaw, L; Birk, DE; Ballas, CB; Whitsitt, JS; Davidson, JM; Hogan, BL
MLA Citation
Liaw, L, Birk, DE, Ballas, CB, Whitsitt, JS, Davidson, JM, and Hogan, BL. "Altered wound healing in mice lacking a functional osteopontin gene (spp1)." J Clin Invest 101.7 (April 1, 1998): 1468-1478.
PMID
9525990
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
101
Issue
7
Publish Date
1998
Start Page
1468
End Page
1478
DOI
10.1172/JCI2131

Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens.

SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin/BM40) is a secreted Ca2+-binding glycoprotein that interacts with a range of extracellular matrix molecules, including collagen IV. It is widely expressed during embryogenesis, and in vitro studies have suggested roles in the regulation of cell adhesion and proliferation, and in the modulation of cytokine activity. In order to analyse the function of this protein in vivo, the endogenous Sparc locus was disrupted by homologous recombination in murine embryonic stem cells. SPARC-deficient mice (Sparctm1Cam) appear normal and fertile until around 6 months of age, when they develop severe eye pathology characterized by cataract formation and rupture of the lens capsule. The first sign of lens pathology occurs in the equatorial bow region where vacuoles gradually form within differentiating epithelial cells and fibre cells. The lens capsule, however, shows no qualitative changes in the major basal lamina proteins laminin, collagen IV, perlecan or entactin. These mice are an excellent resource for further studies on how SPARC affects cell behaviour in vivo.

Authors
Gilmour, DT; Lyon, GJ; Carlton, MB; Sanes, JR; Cunningham, JM; Anderson, JR; Hogan, BL; Evans, MJ; Colledge, WH
MLA Citation
Gilmour, DT, Lyon, GJ, Carlton, MB, Sanes, JR, Cunningham, JM, Anderson, JR, Hogan, BL, Evans, MJ, and Colledge, WH. "Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens." EMBO J 17.7 (April 1, 1998): 1860-1870.
PMID
9524110
Source
pubmed
Published In
EMBO Journal
Volume
17
Issue
7
Publish Date
1998
Start Page
1860
End Page
1870
DOI
10.1093/emboj/17.7.1860

Bone morphogenetic protein 8A plays a role in the maintenance of spermatogenesis and the integrity of the epididymis.

The murine Bmp8a and Bmp8b genes are tightly linked on mouse chromosome 4 and have similar expression during reproduction. Previous studies have shown that targeted mutagenesis of Bmp8b causes male infertility due to germ cell degeneration. To investigate the function of Bmp8a, we have inactivated the gene by homologous recombination. Heterozygous and homozygous Bmp8a mutants reveal normal embryonic and postnatal development. Despite high levels of Bmp8a expression in the deciduum, homozygous mutant females have normal fertility, suggesting that the gene is not essential for female reproduction. Bmp8a and Bmp8b are expressed in similar patterns in male germ cells. Unlike homozygous Bmp8btm1 mutants, homozygous Bmp8atm1 males do not show obvious germ cell defects during the initiation of spermatogenesis. However, germ cell degeneration is observed in 47% of adult homozygous Bmp8atm1 males, establishing a role of Bmp8a in the maintenance of spermatogenesis. A small proportion of the mating homozygous Bmp8atm1 males also show degeneration of the epididymal epithelium, indicating a novel role for BMPs in the control of epididymal function.

Authors
Zhao, GQ; Liaw, L; Hogan, BL
MLA Citation
Zhao, GQ, Liaw, L, and Hogan, BL. "Bone morphogenetic protein 8A plays a role in the maintenance of spermatogenesis and the integrity of the epididymis." Development 125.6 (March 1998): 1103-1112.
PMID
9463357
Source
pubmed
Published In
Development (Cambridge)
Volume
125
Issue
6
Publish Date
1998
Start Page
1103
End Page
1112

Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption.

Chronic volume depletion by dietary salt restriction causes marked decrease in glomerular filtration rate (GFR) with little increase in urine osmolality in angiotensinogen gene null mutant (Agt-/-) mice. Moreover, urine osmolality is insensitive to both water and vasopressin challenge. In contrast, in normal wild-type (Agt+/+) mice, GFR remains remarkably constant and urine osmolality is adjusted promptly. Changes in volume status also cause striking divergence in renal structure between Agt-/- and Agt+/+ mice. Thus, in contrast to the remarkably stable glomerular size of Agt+/+ mice, glomeruli of Agt-/- mice are atrophied during a low salt and hypertrophied during a high salt diet. Moreover, the renal papilla, a structure unique to mammals and essential for urine diluting and concentrating mechanisms, is hypoplastic in Agt-/- mice. Thus, angiotensin is essential for the two fundamental homeostatic functions of the mammalian kidney, namely stable GFR and high urine diluting and concentrating capacity during alteration in extracellular fluid (ECF) volume. This is not only accompanied by angiotensin's tonic effects on renal vasomotor tone and tubule transporters, but also accomplished through its capacity to affect the structure of both the glomerulus and the papilla directly or indirectly.

Authors
Okubo, S; Niimura, F; Matsusaka, T; Fogo, A; Hogan, BL; Ichikawa, I
MLA Citation
Okubo, S, Niimura, F, Matsusaka, T, Fogo, A, Hogan, BL, and Ichikawa, I. "Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption." Kidney Int 53.3 (March 1998): 617-625.
PMID
9507206
Source
pubmed
Published In
Kidney international
Volume
53
Issue
3
Publish Date
1998
Start Page
617
End Page
625
DOI
10.1046/j.1523-1755.1998.00788.x

Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor.

We have taken advantage of an enhancer trap event in a line of transgenic mice to identify a unique developmentally regulated endothelial cell locus (Del1). The protein encoded in this locus contains three EGF-like repeats homologous to those in Notch and related proteins, including an EGF-like repeat that contains an RGD motif, and two discoidin I-like domains. Del1 is shown to be a matrix protein and to promote adhesion of endothelial cells through interaction with the alphavbeta3 integrin receptor. Embryonic endothelial-like yolk sac cells expressing recombinant Del1 protein, or grown on an extracellular matrix containing Del1 protein, are inhibited from forming vascular-like structures. Expression of Del1 protein in the chick chorioallantoic membrane leads to loss of vascular integrity and promotes vessel remodeling. Del1 is thus a new ligand for the alphavbeta3 integrin receptor and may function to regulate vascular morphogenesis or remodeling in embryonic development.

Authors
Hidai, C; Zupancic, T; Penta, K; Mikhail, A; Kawana, M; Quertermous, EE; Aoka, Y; Fukagawa, M; Matsui, Y; Platika, D; Auerbach, R; Hogan, BL; Snodgrass, R; Quertermous, T
MLA Citation
Hidai, C, Zupancic, T, Penta, K, Mikhail, A, Kawana, M, Quertermous, EE, Aoka, Y, Fukagawa, M, Matsui, Y, Platika, D, Auerbach, R, Hogan, BL, Snodgrass, R, and Quertermous, T. "Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor." Genes Dev 12.1 (January 1, 1998): 21-33.
PMID
9420328
Source
pubmed
Published In
Genes & development
Volume
12
Issue
1
Publish Date
1998
Start Page
21
End Page
33

Mouse Mesenchyme forkhead 2 (Mf2): expression, DNA binding and induction by sonic hedgehog during somitogenesis.

Cloning and sequencing of mouse Mf2 (mesoderm/mesenchyme forkhead 2) cDNAs revealed an open reading frame encoding a putative protein of 492 amino acids which, after in vitro translation, binds to a DNA consensus sequence. Mf2 is expressed at high levels in the ventral region of newly formed somites, in sclerotomal derivatives, in lateral plate and cephalic mesoderm and in the first and second branchial arches. Other regions of mesodermal expression include the developing tongue, meninges, nose, whiskers, kidney, genital tubercule and limb joints. In the nervous system Mf2 is transcribed in restricted regions of the mid- and forebrain. In several tissues, including the early somite, Mf2 is expressed in cell populations adjacent to regions expressing sonic hedgehog (Shh) and in explant cultures of presomitic mesoderm Mf2 is induced by Shh secreted by COS cells. These results suggest that Mf2, like other murine forkhead genes, has multiple roles in embryogenesis, possibly mediating the response of cells to signaling molecules such as SHH.

Authors
Wu, SC; Grindley, J; Winnier, GE; Hargett, L; Hogan, BL
MLA Citation
Wu, SC, Grindley, J, Winnier, GE, Hargett, L, and Hogan, BL. "Mouse Mesenchyme forkhead 2 (Mf2): expression, DNA binding and induction by sonic hedgehog during somitogenesis." Mech Dev 70.1-2 (January 1998): 3-13.
PMID
9510020
Source
pubmed
Published In
Mechanisms of Development
Volume
70
Issue
1-2
Publish Date
1998
Start Page
3
End Page
13

Mice lacking Bmp6 function.

Bmp6, a member of the 60A subgroup of bone morphogenetic proteins (BMPs), is expressed in diverse sites in the developing mouse embryo from preimplantation stages onwards. To evaluate roles for Bmp6 signaling in vivo, gene targeting was used to generate a null mutation at the Bmp6 locus. The resulting Bmp6 mutant mice are viable and fertile, and show no overt defects in tissues known to express Bmp6 mRNA. The skeletal elements of newborn and adult mutants are indistinguishable from wild-type. However, careful examination of skeletogenesis in late gestation embryos reveals a consistent delay in ossification strictly confined to the developing sternum. In situ hybridization studies in the developing long bones and sternum show that other BMP family members are expressed in overlapping domains. In particular we find that Bmp2 and Bmp6 are coexpressed in hypertrophic cartilage, suggesting that Bmp2 may functionally compensate in Bmp6 null mice. The defects in sternum development in Bmp6 null mice are likely to be associated with a transient early expression of Bmp6 in the sternal bands, prior to ossification. These sternal defects are slightly exacerbated in Bmp5/6 double mutant animals.

Authors
Solloway, MJ; Dudley, AT; Bikoff, EK; Lyons, KM; Hogan, BL; Robertson, EJ
MLA Citation
Solloway, MJ, Dudley, AT, Bikoff, EK, Lyons, KM, Hogan, BL, and Robertson, EJ. "Mice lacking Bmp6 function." Dev Genet 22.4 (1998): 321-339.
PMID
9664685
Source
pubmed
Published In
Developmental Genetics
Volume
22
Issue
4
Publish Date
1998
Start Page
321
End Page
339
DOI
10.1002/(SICI)1520-6408(1998)22:4<321::AID-DVG3>3.0.CO;2-8

Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice.

Analysis of the skeletal phenotypes caused by the genetic inactivation of individual Bmps, along with the study of their expression patterns, suggest possible functional redundancy of these molecules. To investigate the effect on skeleton development of the combined absence of some Bmp genes expressed in the same areas, we have intercrossed heterozygous Bmp7 mice with Bmp2 +/-, Bmp4 +/-, or Bmp5 +/- animals. Bmp2/7 and Bmp5/7 double heterozygous animals do not present with any abnormalities. In contrast, Bmp4/7 double heterozygotes develop minor defects in two restricted areas of the skeleton, the rib cage, and the distal part of the limbs. In the ribs, Bmp4 and Bmp7 seem to act in the same pathway to assure proper guidance of mesenchymal condensations of the ribs extending toward the sternum. In the limbs, these molecules appear to play a similar role in controlling digit number, possibly through induction of apoptosis in the interdigital and anterior mesenchyme.

Authors
Katagiri, T; Boorla, S; Frendo, JL; Hogan, BL; Karsenty, G
MLA Citation
Katagiri, T, Boorla, S, Frendo, JL, Hogan, BL, and Karsenty, G. "Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice." Dev Genet 22.4 (1998): 340-348.
PMID
9664686
Source
pubmed
Published In
Developmental Genetics
Volume
22
Issue
4
Publish Date
1998
Start Page
340
End Page
348
DOI
10.1002/(SICI)1520-6408(1998)22:4<340::AID-DVG4>3.0.CO;2-6

Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo

In mammals, 16 members of the Fgf family have so far been described with diverse roles in embryonic cell growth and differentiation. Here, we report the expression from early streak stage to midgestation of two newly- identified murine genes, Fgf17 and Fgf18, that are most closely related to Fgf8 (63.7% and 56.8% identical, respectively, at the amino acid level). Fgf17 is expressed during gastrulation but at lower levels than Fgf8, while Fgf18 RNA is not expressed until later, in paraxial mesoderm. In the developing tail bud, each Fgf gene shows a different pattern of transcription. Distinct and overlapping expression patterns are also described in the developing brain and limbs.

Authors
Maruoka, Y; Ohbayashi, N; Hoshikawa, M; Itoh, N; Hogan, BLM; Furuta, Y
MLA Citation
Maruoka, Y, Ohbayashi, N, Hoshikawa, M, Itoh, N, Hogan, BLM, and Furuta, Y. "Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo." Mechanisms of Development 74.1-2 (1998): 175-177.
PMID
9651520
Source
scival
Published In
Mechanisms of Development
Volume
74
Issue
1-2
Publish Date
1998
Start Page
175
End Page
177
DOI
10.1016/S0925-4773(98)00061-6

Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung.

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48-60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.

Authors
Bellusci, S; Grindley, J; Emoto, H; Itoh, N; Hogan, BL
MLA Citation
Bellusci, S, Grindley, J, Emoto, H, Itoh, N, and Hogan, BL. "Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung." Development 124.23 (December 1997): 4867-4878.
PMID
9428423
Source
pubmed
Published In
Development (Cambridge)
Volume
124
Issue
23
Publish Date
1997
Start Page
4867
End Page
4878

Evidence for the involvement of the Gli gene family in embryonic mouse lung development.

Murine Gli, Gli2, and Gli3 are zinc finger genes related to Drosophila cubitus interuptus, a component of the hedgehog signal transduction pathway. In the embryonic lung, all three Gli genes are strongly expressed at the pseudoglandular stage, in distinct but overlapping domains of the mesoderm. Expression of Gli and Gli3, but not of Gli2, is subsequently downregulated at the canalicular stage, coincident with a decline in the expression of sonic hedgehog (Shh) and the hedgehog receptor gene, patched (Ptc). Overexpression of Shh in the lung results in increased levels of Ptc mRNA. Gli, but not Gli2, is also upregulated, suggesting a differential involvement of the Gli genes in the regulation of Ptc by SHH during lung development. Gli3 is not upregulated by Shh overexpression. However, its importance for lung development is shown by the finding that Gli3XtJ embryos, homozygous for a mutation involving a deletion of the Gli3 gene, have a stereotypic pattern of abnormalities in lung morphogenesis. The pulmonary defects in these embryos, consisting of localized shape changes and size reductions, correlate with normal Gli3 expression. Thus, our data indicate that one of the Gli genes, Gli3, is essential for normal lung development, and that another, Gli, can be placed downstream of Shh signaling in the lung.

Authors
Grindley, JC; Bellusci, S; Perkins, D; Hogan, BL
MLA Citation
Grindley, JC, Bellusci, S, Perkins, D, and Hogan, BL. "Evidence for the involvement of the Gli gene family in embryonic mouse lung development." Dev Biol 188.2 (August 15, 1997): 337-348.
PMID
9268579
Source
pubmed
Published In
Developmental Biology
Volume
188
Issue
2
Publish Date
1997
Start Page
337
End Page
348
DOI
10.1006/dbio.1997.8644

Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4.

Bone morphogenetic protein 4 (Bmp4), a vertebrate homolog of Drosophila decapentaplegic (dpp), encodes a signaling protein with multiple functions during embryogenesis. Most mouse embryos homozygous for the Bmp4(tm1blh) null allele die around the time of gastrulation, with little or no mesoderm. Two independently derived Bmp4(tm1) mutations were backcrossed onto the C57BL/6 genetic background. Several independently expressed, incompletely penetrant abnormalities were observed in heterozygotes, including cystic kidney, craniofacial malformations, microphthalmia, and preaxial polydactyly of the right hindlimb. In addition, heterozygotes were consistently underrepresented at weaning. These results indicate that Bmp4 gene dosage is essential for the normal development of a variety of organs and for neonatal viability. Two mutations that enhance the penetrance and expressivity of the polydactylous phenotype were identified: Gli3(XtJ), a deletion mutation involving a gene encoding a zinc-finger protein related to Drosophila cubitus interruptus, and Alx4(tm1rwm), a targeted null mutation in a gene encoding a paired class homeoprotein related to Drosophila aristaless. All double Bmp4(tm1); Gli3(XtJ) heterozygotes have extensive anterior digit abnormalities of both fore- and hindlimbs, while all double Bmp4(tm1); Alx4(tm1) heterozygotes display ectopic anterior digits only on the hindlimbs. These genetic interactions suggest a model for the multigenic control of anterior digit patterning during vertebrate limb development.

Authors
Dunn, NR; Winnier, GE; Hargett, LK; Schrick, JJ; Fogo, AB; Hogan, BL
MLA Citation
Dunn, NR, Winnier, GE, Hargett, LK, Schrick, JJ, Fogo, AB, and Hogan, BL. "Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4." Dev Biol 188.2 (August 15, 1997): 235-247.
PMID
9268572
Source
pubmed
Published In
Developmental Biology
Volume
188
Issue
2
Publish Date
1997
Start Page
235
End Page
247
DOI
10.1006/dbio.1997.8664

Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development.

Bone Morphogenetic Proteins (BMPs) play crucial roles in a variety of developmental processes, but their functions during early vertebrate brain development are largely unknown. To investigate this problem, we have compared by in situ hybridization the expression of five Bmp genes belonging to the Drosophila Decapentaplegic (Bmp2 and Bmp4) and 60A subgroups (Bmp5, Bmp6 and Bmp7). Striking co-expression of these Bmps is observed within the dorsomedial telencephalon, coincident with a future site of choroid plexus development. Bmp co-expression overlaps that of Msx1 and Hfh4, and is complementary to that of Bf1. The domain of Bmp co-expression is also associated with limited growth of the neuroectoderm, as revealed by morphological observation, reduced cell proliferation, and increased local programmed cell death. In vitro experiments using explants from the embryonic lateral telencephalic neuroectoderm reveal that exogenous BMP proteins (BMP4 and BMP2) induce expression of Msx1 and inhibit Bf1 expression, a finding consistent with their specific expression patterns in vivo. Moreover, BMP proteins locally inhibit cell proliferation and increase apoptosis in the explants. These results provide evidence that BMPs function during regional morphogenesis of the dorsal telencephalon by regulating specific gene expression, cell proliferation and local cell death.

Authors
Furuta, Y; Piston, DW; Hogan, BL
MLA Citation
Furuta, Y, Piston, DW, and Hogan, BL. "Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development." Development 124.11 (June 1997): 2203-2212.
PMID
9187146
Source
pubmed
Published In
Development (Cambridge)
Volume
124
Issue
11
Publish Date
1997
Start Page
2203
End Page
2212

Disruption of PAX6 function in mice homozygous for the Pax6Sey-1Neu mutation produces abnormalities in the early development and regionalization of the diencephalon.

Pax6 expression in the diencephalon of the mouse embryo is restricted both antero-posteriorly and dorso-ventrally, with changes in level occurring at prosomere boundaries. Small eye (Pax6Sey-1Neu) mice homozygous for Pax6 mutations have multiple defects in early forebrain development. In the diencephalon of Pax6Sey-1Neu/Pax6Sey-1Neu mice there is an apparent enlargement of the zona limitans (the boundary region between prosomeres p2 and p3), and a blurring of the p1-p2 boundary. PAX6 function is also required for the normal development of the posterior commissure at the midbrain-p1 boundary. In the posterior diencephalon PAX6 appears to regulate its own transcription, and that of Wnt7b. In p2 and p3, ventral markers are expressed more dorsally than normal, and this is accompanied in p3 by a reduction in the size of the zona incerta. Thus, PAX6 is essential for the normal development and regionalization of the diencephalon.

Authors
Grindley, JC; Hargett, LK; Hill, RE; Ross, A; Hogan, BL
MLA Citation
Grindley, JC, Hargett, LK, Hill, RE, Ross, A, and Hogan, BL. "Disruption of PAX6 function in mice homozygous for the Pax6Sey-1Neu mutation produces abnormalities in the early development and regionalization of the diencephalon." Mech Dev 64.1-2 (June 1997): 111-126.
PMID
9232602
Source
pubmed
Published In
Mechanisms of Development
Volume
64
Issue
1-2
Publish Date
1997
Start Page
111
End Page
126

The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo.

The gene mfh1, encoding a winged helix/forkhead domain transcription factor, is expressed in a dynamic pattern in paraxial and presomitic mesoderm and developing somites during mouse embryogenesis. Expression later becomes restricted to condensing mesenchyme of the vertebrae, head, limbs, and kidney. A targeted disruption of the gene was generated by homologous recombination in embryonic stem cells. Most homozygous mfh1 null embryos die prenatally but some survive to birth, with multiple craniofacial and vertebral column defects. Using molecular markers, we show that the initial formation and patterning of somites occurs normally in mutants. Differentiation of sclerotome-derived cells also appears unaffected, although a reduction of the level of some markers [e.g., mtwist, mf1, scleraxis, and alpha1(II) collagen] is seen in the anterior of homozygous mutants. The most significant difference, however, is a marked reduction in the proliferation of sclerotome-derived cells, as judged by BrdU incorporation. This proliferation defect was also seen in micromass cultures of somite-derived cells treated with transforming growth factor beta1 and fibroblast growth factors. Our findings establish a requirement for a winged helix/forkhead domain transcription factor in the development of the paraxial mesoderm. A model is proposed for the role of mfh1 in regulating the proliferation and differentiation of cell lineages giving rise to the axial skeleton and skull.

Authors
Winnier, GE; Hargett, L; Hogan, BL
MLA Citation
Winnier, GE, Hargett, L, and Hogan, BL. "The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo." Genes Dev 11.7 (April 1, 1997): 926-940.
PMID
9106663
Source
pubmed
Published In
Genes & development
Volume
11
Issue
7
Publish Date
1997
Start Page
926
End Page
940

The winged helix gene, Mf3, is required for normal development of the diencephalon and midbrain, postnatal growth and the milk-ejection reflex.

The mouse Mf3 gene, also known as Fkh5 and HFH-e5.1, encodes a winged helix/forkhead transcription factor. In the early embryo, transcripts for Mf3 are restricted to the presomitic mesoderm and anterior neurectoderm and mesoderm. By 9.5 days post coitum, expression in the nervous system is predominantly in the diencephalon, midbrain and neural tube. After midgestation, the highest level of mRNA is in the mammillary bodies, the posterior-most part of the hypothalamus. Mice homozygous for a deletion of the mf3 locus on a [129 x Black Swiss] background display variable phenotypes consistent with a requirement for the gene at several stages of embryonic and postnatal development. Approximately six percent of the mf3-/- embryos show an open neural tube in the diencephalon and midbrain region, and another five percent show a severe reduction of the posterior body axis; both these classes of affected embryos die in utero. Surviving homozygotes have an apparently normal phenotype at birth. Postnatally, however, mf3-/- pups are severely growth retarded and approximately one third die before weaning. This growth defect is not a direct result of lack of circulating growth hormone or thyrotropin. Mice that survive to weaning are healthy, but they show an abnormal clasping of the hindfeet when suspended by the tail. Although much smaller than normal, the mice are fertile. However, mf3-/- females cannot eject their milk supply to feed their pups. This nursing defect can be corrected with interperitoneal injections of oxytocin. These results provide evidence that Mf3 is required for normal hypothalamus development and suggest that Mf3 may play a role in postnatal growth and lactation.

Authors
Labosky, PA; Winnier, GE; Jetton, TL; Hargett, L; Ryan, AK; Rosenfeld, MG; Parlow, AF; Hogan, BL
MLA Citation
Labosky, PA, Winnier, GE, Jetton, TL, Hargett, L, Ryan, AK, Rosenfeld, MG, Parlow, AF, and Hogan, BL. "The winged helix gene, Mf3, is required for normal development of the diencephalon and midbrain, postnatal growth and the milk-ejection reflex." Development 124.7 (April 1997): 1263-1274.
PMID
9118797
Source
pubmed
Published In
Development (Cambridge)
Volume
124
Issue
7
Publish Date
1997
Start Page
1263
End Page
1274

The bZIP transcription factor LCR-F1 is essential for mesoderm formation in mouse development.

LCR-F1 is a mammalian bZIP transcription factor containing a basic amino acid domain highly homologous to a domain in the Drosophila Cap 'N' Collar and Caenorhabditis elegans SKN-1 proteins. LCR-F1 binds to AP1-like sequences in the human beta-globin locus control region and activates high-level expression of beta-globin genes. To assess the role of LCR-F1 in mammalian development, the mouse Lcrf1 gene was deleted in embryonic stem (ES) cells, and mice derived from these cells were mated to produce Lcrf1 null animals. Homozygous mutant embryos progressed normally to the late egg cylinder stage at approximately 6.5 days post coitus (dpc), but development was arrested before 7.5 dpc. Lcrf1 mutant embryos failed to form a primitive streak and lacked detectable mesoderm. These results demonstrate that LCR-F1 is essential for gastrulation in the mouse and suggest that this transcription factor controls expression of genes critical for the earliest events in mesoderm formation. Interestingly, Lcrf1 null ES cells injected into wild-type blastocysts contributed to all mesodermally derived tissues examined, including erythroid cells producing hemoglobin. These results demonstrate that the Lcrf1 mutation is not cell autonomous and suggest that LCR-F1 regulates expression of signaling molecules essential for gastrulation. The synthesis of normal hemoglobin levels in erythroid cells of chimeras derived from Lcrf1 null cells suggests that LCR-F1 is not essential for globin gene expression. LCR-F1 and the related bZIP transcription factors NF-E2 p45 and NRF2 must compensate for each other in globin gene regulation.

Authors
Farmer, SC; Sun, CW; Winnier, GE; Hogan, BL; Townes, TM
MLA Citation
Farmer, SC, Sun, CW, Winnier, GE, Hogan, BL, and Townes, TM. "The bZIP transcription factor LCR-F1 is essential for mesoderm formation in mouse development." Genes Dev 11.6 (March 15, 1997): 786-798.
PMID
9087432
Source
pubmed
Published In
Genes & development
Volume
11
Issue
6
Publish Date
1997
Start Page
786
End Page
798

Structure and sequence of the mouse Bmp6 gene.

Authors
Gitelman, SE; Kobrin, M; Lee, A; Fet, V; Lyons, K; Hogan, BL; Derynck, R
MLA Citation
Gitelman, SE, Kobrin, M, Lee, A, Fet, V, Lyons, K, Hogan, BL, and Derynck, R. "Structure and sequence of the mouse Bmp6 gene." Mamm Genome 8.3 (March 1997): 212-214.
PMID
9069123
Source
pubmed
Published In
Mammalian Genome
Volume
8
Issue
3
Publish Date
1997
Start Page
212
End Page
214

Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin.

Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors. We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the ApcMin allele (Min/+) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min/+ mice deficient in this MMP by gene targeting and homologous recombination. The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min/+ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation. These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.

Authors
Wilson, CL; Heppner, KJ; Labosky, PA; Hogan, BL; Matrisian, LM
MLA Citation
Wilson, CL, Heppner, KJ, Labosky, PA, Hogan, BL, and Matrisian, LM. "Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin." Proc Natl Acad Sci U S A 94.4 (February 18, 1997): 1402-1407.
PMID
9037065
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
4
Publish Date
1997
Start Page
1402
End Page
1407

Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.

Branching morphogenesis of the embryonic lung requires interactions between the epithelium and the mesenchyme. Previously, we reported that Sonic hedgehog (Shh) transcripts are present in the epithelium of the developing mouse lung, with highest levels in the terminal buds. Here, we report that transcripts of mouse patched (Ptc), the homologue of a Drosophila gene encoding a putative transmembrane protein required for hedgehog signaling, are expressed at high levels in the mesenchyme adjacent to the end buds. To investigate the function of SHH in lung development, Shh was overexpressed throughout the distal epithelium, using the surfactant protein-C (SP-C)-enhancer/promoter. Beginning around 16.5 dpc, when Shh and Ptc RNA levels are normally both declining, this treatment caused an increase in the ratio of interstitial mesenchyme to epithelial tubules in transgenic compared to normal lungs. Transgenic newborn mice die soon after birth. Histological analysis of the lungs at the light and electron microscope level shows an abundance of mesenchyme and the absence of typical alveoli. In vivo BrdU labeling indicates that Shh overexpression results in increased mesenchymal and epithelial cell proliferation at 16.5 and 17.5 dpc. However, analysis of CC-10 and SP-C expression reveals no significant inhibition in the differentiation of proximal and distal epithelial cells. The expression of genes potentially regulated by SHH was also examined. No difference could be observed between transgenic and control lungs in either the level or distribution of Bmp4, Wnt2 and Fgf7 RNA. By contrast, Ptc is clearly upregulated in the transgenic lung. These results thus establish a role for SHH in lung morphogenesis, and suggest that SHH normally regulates lung mesenchymal cell proliferation in vivo.

Authors
Bellusci, S; Furuta, Y; Rush, MG; Henderson, R; Winnier, G; Hogan, BL
MLA Citation
Bellusci, S, Furuta, Y, Rush, MG, Henderson, R, Winnier, G, and Hogan, BL. "Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis." Development 124.1 (January 1997): 53-63.
PMID
9006067
Source
pubmed
Published In
Development (Cambridge)
Volume
124
Issue
1
Publish Date
1997
Start Page
53
End Page
63

Evidence that Mothers-against-dpp-related 1 (Madr1) plays a role in the initiation and maintenance of spermatogenesis in the mouse.

We have cloned a mouse cDNA encoding a Mothers-against-dpp (MAD)-related protein, MADR1. Madr1 is ubiquitously expressed in the mouse embryo, indicating a broad function in a variety of tissue during embryogenesis, potentially relaying signals of numerous BMPs. However, its expression in the testis is strictly germ cell-specific and developmentally regulated. Testicular Madr1 expression starts in some seminiferous tubules at 2 weeks of age. After mid-puberty, a stage-specific Madr1 expression is established. During the cycling of the seminiferous epithelium, Madr1 expression initiates in the pachytene spermatocytes of stage V seminiferous tubules, peaks at stage X, then decreases as pachytene spermatocytes differentiate into secondary spermatocytes and then round spermatids. In the testis of adult Bmp8b homozygous mutant males, the Madr1- expressing pachytene spermatocytes are the first cell population to show increased apoptosis. These data suggest that MADR1 serves as a downstream component of the BMP8 signaling pathway during the differentiation of meiotic male germ cells.

Authors
Zhao, GQ; Hogan, BL
MLA Citation
Zhao, GQ, and Hogan, BL. "Evidence that Mothers-against-dpp-related 1 (Madr1) plays a role in the initiation and maintenance of spermatogenesis in the mouse." Mech Dev 61.1-2 (January 1997): 63-73.
PMID
9076678
Source
pubmed
Published In
Mechanisms of Development
Volume
61
Issue
1-2
Publish Date
1997
Start Page
63
End Page
73

Branching morphogenesis of the lung: new models for a classical problem.

Authors
Hogan, BL; Grindley, J; Bellusci, S; Dunn, NR; Emoto, H; Itoh, N
MLA Citation
Hogan, BL, Grindley, J, Bellusci, S, Dunn, NR, Emoto, H, and Itoh, N. "Branching morphogenesis of the lung: new models for a classical problem." Cold Spring Harb Symp Quant Biol 62 (1997): 249-256. (Review)
PMID
9598358
Source
pubmed
Published In
Cold Spring Harbor Laboratory: Symposia on Quantitative Biology
Volume
62
Publish Date
1997
Start Page
249
End Page
256

Pattern formation

Authors
Woychik, R; Hogan, B; Bryant, S; Eichele, G; Kimelman, D; Noden, D; Schoenwolf, G; Wright, C
MLA Citation
Woychik, R, Hogan, B, Bryant, S, Eichele, G, Kimelman, D, Noden, D, Schoenwolf, G, and Wright, C. "Pattern formation." Reproductive Toxicology 11.2-3 (1997): 339-344.
PMID
9100309
Source
scival
Published In
Reproductive Toxicology
Volume
11
Issue
2-3
Publish Date
1997
Start Page
339
End Page
344
DOI
10.1016/S0890-6238(96)00217-1

Failure of ventral body wall closure in mouse embryos lacking a procollagen C-proteinase encoded by Bmp1, a mammalian gene related to Drosophila tolloid.

The mouse bone morphogenetic protein1 (Bmp1) gene encodes a secreted astacin metalloprotease that cleaves the COOH-propeptide of procollagen I, II and III. BMP-1 is also related to the product of the Drosophila patterning gene, tolloid (tld), which enhances the activity of the TGFbeta-related growth factor Decapentaplegic and promotes development of the dorsalmost amnioserosa. We have disrupted the mouse Bmp1 gene by deleting DNA sequences encoding the active site of the astacin-like protease domain common to all splice variants. Homozygous mutant embryos appear to have a normal skeleton, apart from reduced ossification of certain skull bones. However, they have a persistent herniation of the gut in the umbilical region and do not survive beyond birth. Analysis of the amnion of homozygous mutant embryos reveals the absence of the fold that normally tightly encloses the physiological hernia of the gut. At the electron microscopic level, the extracellular matrix of the amnion contains collagen fibrils with an abnormal morphology, consistent with the incorporation of partially processed procollagen molecules. Metabolical labelling and immunofluorescence studies also reveal abnormal processing and deposition of procollagen by homozygous mutant fibroblasts in culture.

Authors
Suzuki, N; Labosky, PA; Furuta, Y; Hargett, L; Dunn, R; Fogo, AB; Takahara, K; Peters, DM; Greenspan, DS; Hogan, BL
MLA Citation
Suzuki, N, Labosky, PA, Furuta, Y, Hargett, L, Dunn, R, Fogo, AB, Takahara, K, Peters, DM, Greenspan, DS, and Hogan, BL. "Failure of ventral body wall closure in mouse embryos lacking a procollagen C-proteinase encoded by Bmp1, a mammalian gene related to Drosophila tolloid." Development 122.11 (November 1996): 3587-3595.
PMID
8951074
Source
pubmed
Published In
Development (Cambridge)
Volume
122
Issue
11
Publish Date
1996
Start Page
3587
End Page
3595

Bone morphogenetic proteins in development.

The bone morphogenetic proteins (BMPs) constitute a large family of cytokines related to members of the transforming growth factor-beta superfamily. Recent evidence, in particular from gene targeting experiments in the mouse, indicates that BMPs are required for mesoderm formation and for the development and patterning of many different organ systems. Significant progress has also been made in understanding the role of BMPs in gastrulation and neurulation in Xenopus and in identifying genes regulating BMP expression and components of the downstream signaling pathways. Extracellular modifiers of BMP activity may constitute an opposing morphogenetic system.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Bone morphogenetic proteins in development." Curr Opin Genet Dev 6.4 (August 1996): 432-438. (Review)
PMID
8791534
Source
pubmed
Published In
Current Opinion in Genetics & Development
Volume
6
Issue
4
Publish Date
1996
Start Page
432
End Page
438

Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Bone morphogenetic proteins: multifunctional regulators of vertebrate development." Genes Dev 10.13 (July 1, 1996): 1580-1594. (Review)
PMID
8682290
Source
pubmed
Published In
Genes & development
Volume
10
Issue
13
Publish Date
1996
Start Page
1580
End Page
1594

The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse.

Bone morphogenetic protein 8B (BMP8B) is a member of the TGFbeta superfamily of growth factors. In the mouse, Bmp8b is expressed in male germ cells of the testis and trophoblast cells of the placenta, suggesting that it has a role in spermatogenesis and reproduction. To investigate these possibilities, we have generated mice with a targeted mutation in Bmp8b. Here, we show that homozygous Bmp8b(tm1blh) mutant males exhibit variable degrees of germ-cell deficiency and infertility. Detailed analysis reveals two separable defects in the homozygous mutant testes. First, during early puberty (2 weeks old or younger) the germ cells of all homozygous mutants either fail to proliferate or show a marked reduction in proliferation and a delayed differentiation. Second, in adults, there is a significant increase in programmed cell death (apoptosis) of spermatocytes, leading to germ-cell depletion and sterility. Sertoli cells and Leydig cells appear relatively unaffected in mutants. This study therefore provides the first genetic evidence that a murine germ cell-produced factor, BMP8B, is required for the resumption of male germ-cell proliferation in early puberty, and for germ-cell survival and fertility in the adult.

Authors
Zhao, GQ; Deng, K; Labosky, PA; Liaw, L; Hogan, BL
MLA Citation
Zhao, GQ, Deng, K, Labosky, PA, Liaw, L, and Hogan, BL. "The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse." Genes Dev 10.13 (July 1, 1996): 1657-1669.
PMID
8682296
Source
pubmed
Published In
Genes & development
Volume
10
Issue
13
Publish Date
1996
Start Page
1657
End Page
1669

Evidence that mouse Bmp8a (Op2) and Bmp8b are duplicated genes that play a role in spermatogenesis and placental development.

We have identified two highly conserved mouse genes encoding bone morphogenetic protein 8A (BMP8A/OP2) and 8B (BMP8B). The two loci are tightly linked on chromosome 4, suggesting that they arose through a recent gene duplication. Contrary to previous reports, neither gene is expressed in the early postimplantation mouse embryo (7.5-10.5 days post coitum) as judged by a variety of sensitive techniques. By contrast, high levels of Bmp8b RNA are found in the decidual cells of the uterus, and both genes are expressed in the trophoblast cells of the labyrinthine region of the placenta and in the inner root sheath of hair follicles of early postnatal skin. In addition, both Bmp8a and Bmp8b are expressed in the testis during specific stages of spermatogenesis, with the highest levels of RNA in stage 6-8 round spermatids after 3 weeks of age. Bmp8a and 8b are, therefore, the first members of the transforming growth factor beta (TGF beta)-related gene family to be found expressed in the germ cells of the testis, rather than in the somatic Sertoli cells. These results suggest that Bmp8a and 8b are not required for development of the embryo proper but regulate aspects of cell proliferation, survival and/or differentiation during spermatogenesis and placentation.

Authors
Zhao, GQ; Hogan, BL
MLA Citation
Zhao, GQ, and Hogan, BL. "Evidence that mouse Bmp8a (Op2) and Bmp8b are duplicated genes that play a role in spermatogenesis and placental development." Mech Dev 57.2 (July 1996): 159-168.
PMID
8843393
Source
pubmed
Published In
Mechanisms of Development
Volume
57
Issue
2
Publish Date
1996
Start Page
159
End Page
168

The chromosomal mapping of four genes encoding winged helix proteins expressed early in mouse development.

Members of the winged helix family of transcription factors are required for the normal embryonic development of the mouse. Using the interspecific backcross panel from The Jackson Laboratory, we have determined the chromosomal locations of four genes that encode winged helix containing proteins. Mf1 was assigned to mouse Chromosome 8, Mf2 to Chromosome 4, Mf3 to Chromosome 9, and Mf4 to Chromosome 13. Since Mf3 is located in a region of Chromosome 9 containing many well-characterized mouse mutations such as short ear (se), ashen (ash), and dilute (d), we have analyzed deletion mutants to determine the location of Mf3 more precisely.

Authors
Labosky, PA; Winnier, GE; Sasaki, H; Blessing, M; Hogan, BL
MLA Citation
Labosky, PA, Winnier, GE, Sasaki, H, Blessing, M, and Hogan, BL. "The chromosomal mapping of four genes encoding winged helix proteins expressed early in mouse development." Genomics 34.2 (June 1, 1996): 241-245.
PMID
8661058
Source
pubmed
Published In
Genomics
Volume
34
Issue
2
Publish Date
1996
Start Page
241
End Page
245
DOI
10.1006/geno.1996.0275

Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis.

Epithelial-mesenchymal interactions are critical for the branching and differentiation of the lung, but the mechanisms involved are still unclear. To investigate this problem in mouse embryonic lung, we have studied the temporal and spatial expression of genes implicated in the morphogenesis of other organs. At 11.5 days p.c., hepatocyte nuclear factor-3beta (Hnf-3beta) is expressed uniformly throughout the epithelium, while Wnt-2 expression is confined to the distal mesenchyme. Sonic hedgehog (Shh) transcripts are found throughout the epithelium, with high levels in the distal tips of the terminal buds, while bone morphogenetic protein-4 (Bmp-4) transcripts are localized at high levels in the distal tips of the epithelium, with lower levels in the adjacent mesenchyme. Epithelial expression is also seen for Bmp-7, but transcripts are less dramatically upregulated at the distal tips. The Type I Bone morphogenetic protein receptor gene (Bmpr/Tfr-11/Brk-1) is expressed at low levels in the epithelium and in the distal mesenchyme. To investigate the role of Bmp-4 in lung development, we have misexpressed the gene throughout the distal epithelium of transgenic lungs using a surfactant protein C enhancer/promoter. From 15.5 days p.c., transgenic lungs are smaller than normal, with grossly distended terminal buds and, at birth, contain large air-filled sacs which do not support normal lung function. Labeling with BrdU reveals an inhibition of epithelia] proliferation in 15.5 days p.c. transgenic lungs. A small but significant stimulation of proliferation of mesenchymal cells is also observed, but this is accompanied by an increase in cell death. In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs. A model is proposed for the role of BMP4 and other signalling molecules in embryonic lung morphogenesis.

Authors
Bellusci, S; Henderson, R; Winnier, G; Oikawa, T; Hogan, BL
MLA Citation
Bellusci, S, Henderson, R, Winnier, G, Oikawa, T, and Hogan, BL. "Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis." Development 122.6 (June 1996): 1693-1702.
PMID
8674409
Source
pubmed
Published In
Development (Cambridge)
Volume
122
Issue
6
Publish Date
1996
Start Page
1693
End Page
1702

Bone morphogenetic protein-4 (BMP-4) acts during gastrula stages to cause ventralization of Xenopus embryos.

Injection of RNA encoding BMP-4 into the early Xenopus embryo suppresses formation of dorsal and anterior cell types. To understand this phenomenon, it is necessary to know the stage at which BMP-4 acts. In this paper, we present three lines of evidence showing that BMP-4 misexpression has no effect on the initial steps of mesoderm induction, either dorsal or ventral, but instead causes ventralization during gastrulation. Firstly, activation of organizer-specific genes such as goosecoid, Xnot, pintallavis and noggin occurs normally in embryos injected with BMP-4 RNA, but transcript levels are then rapidly down-regulated as gastrulation proceeds. Similarly, BMP-4 does not affect the initial activation of goosecoid by activin in animal caps, but expression then declines precipitously. Secondly, embryos made ventral by injection with BMP-4 RNA cannot be rescued by grafts of Spemann's organizer at gastrula stages. Such embryos therefore differ from those made ventral by UV-irradiation, where the defect occurs early and rescue can be effected by the organizer. Finally, the dorsalizing effects of the organizer, and of the candidate dorsalizing signal noggin, both of which exert their effects during gastrulation, can be counteracted by BMP-4. Together, these experiments demonstrate that BMP-4 can act during gastrulation both to promote ventral mesoderm differentiation and to attenuate dorsalizing signals derived from the organizer.

Authors
Jones, CM; Dale, L; Hogan, BL; Wright, CV; Smith, JC
MLA Citation
Jones, CM, Dale, L, Hogan, BL, Wright, CV, and Smith, JC. "Bone morphogenetic protein-4 (BMP-4) acts during gastrula stages to cause ventralization of Xenopus embryos." Development 122.5 (May 1996): 1545-1554.
PMID
8625841
Source
pubmed
Published In
Development (Cambridge)
Volume
122
Issue
5
Publish Date
1996
Start Page
1545
End Page
1554

PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.

It has been proposed that the Xenopus homeobox gene, XlHbox8, is involved in endodermal differentiation during pancreatic and duodenal development (Wright, C.V.E., Schnegelsberg, P. and De Robertis, E.M. (1988). Development 105, 787-794). To test this hypothesis directly, gene targeting was used to make two different null mutations in the mouse XlHbox8 homolog, pdx-1. In the first, the second pdx-1 exon, including the homeobox, was replaced by a neomycin resistance cassette. In the second, a lacZ reporter was fused in-frame with the N terminus of PDX-1, replacing most of the homeodomain. Neonatal pdx-1 -/- mice are apancreatic, in confirmation of previous reports (Jonsson, J., Carlsson, L., Edlund, T. and Edlund, H. (1994). Nature 371, 606-609). However, the pancreatic buds do form in homozygous mutants, and the dorsal bud undergoes limited proliferation and outgrowth to form a small, irregularly branched, ductular tree. This outgrowth does not contain insulin or amylase-positive cells, but glucagon-expressing cells are found. The rostral duodenum shows a local absence of the normal columnar epithelial lining, villi, and Brunner's glands, which are replaced by a GLUT2-positive cuboidal epithelium resembling the bile duct lining. Just distal of the abnormal epithelium, the numbers of enteroendocrine cells in the villi are greatly reduced. The PDX-1/beta-galactosidase fusion allele is expressed in pancreatic and duodenal cells in the absence of functional PDX-1, with expression continuing into perinatal stages with similar boundaries and expression levels. These results offer additional insight into the role of pdx-1 in the determination and differentiation of the posterior foregut, particularly regarding the proliferation and differentiation of the pancreatic progenitors.

Authors
Offield, MF; Jetton, TL; Labosky, PA; Ray, M; Stein, RW; Magnuson, MA; Hogan, BL; Wright, CV
MLA Citation
Offield, MF, Jetton, TL, Labosky, PA, Ray, M, Stein, RW, Magnuson, MA, Hogan, BL, and Wright, CV. "PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum." Development 122.3 (March 1996): 983-995.
PMID
8631275
Source
pubmed
Published In
Development (Cambridge)
Volume
122
Issue
3
Publish Date
1996
Start Page
983
End Page
995

Enhancer analysis of the mouse HNF-3 beta gene: regulatory elements for node/notochord and floor plate are independent and consist of multiple sub-elements.

BACKGROUND: Axial pattern formation in vertebrate embryos depends on signals from the node and, later, from the notochord and floor plate. Previous studies have shown that HNF-3 beta, a member of the winged-helix transcription factor family, plays key roles in the development of all three organizing centres. RESULTS: Enhancer analysis of HNF-3 beta has therefore been performed using lacZ reporter gene constructs in transgenic mouse embryos. This has led to the identification of independent node/notochord and floor plate enhancers, at positions far upstream (-15 to -14 kb) and downstream (+6 to +11 kb) of the transcription star site, respectively. The node/notochord enhancer activity has been localized to a 520 bp fragment. Floor plate gene expression requires a combination of two separate fragments of the enhancer. Deletion analysis of one of these fragments (400 bp) has identified subregions required for the initiation and the maintenance of floor plate expression, and for the suppression of ectopic expression within the neural tube. CONCLUSION: We conclude that HNF-3 beta gene expression in the node/notochord and in the floor plate are controlled through different enhancers, which consist of positive and negative elements.

Authors
Sasaki, H; Hogan, BL
MLA Citation
Sasaki, H, and Hogan, BL. "Enhancer analysis of the mouse HNF-3 beta gene: regulatory elements for node/notochord and floor plate are independent and consist of multiple sub-elements." Genes Cells 1.1 (January 1996): 59-72.
PMID
9078367
Source
pubmed
Published In
Genes to Cells
Volume
1
Issue
1
Publish Date
1996
Start Page
59
End Page
72

Bmps: multifunctional regulators of mammalian embryonic development.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Bmps: multifunctional regulators of mammalian embryonic development." Harvey lectures 92 (1996): 83-98.
PMID
15372745
Source
scival
Published In
Harvey lectures
Volume
92
Publish Date
1996
Start Page
83
End Page
98

Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation.

Mouse embryos homozygous for a null mutation in nodal arrest development at early gastrulation and contain little or no embryonic mesoderm. Here, two Xenopus nodal-related genes (Xnr-1 and Xnr-2) are identified and shown to be expressed transiently during embryogenesis, first within the vegetal region of late blastulae and later in the marginal zone during gastrulation, with enrichment in the dorsal lip. Xnrs and mouse nodal function as dose-dependent dorsoanterior and ventral mesoderm inducers in whole embryos and explanted animal caps. Using a plasmid vector to produce Xnr proteins during gastrulation, we show that, in contrast to activin and other TGF beta-like molecules, Xnr-1 and Xnr-2 can dorsalize ventral marginal zone explants and induce muscle differentiation. Xnr signalling also rescues a complete embryonic axis in UV-ventralized embryos. The patterns of Xnr expression, the activities of the proteins and the phenotype of mouse nodal mutants, all argue strongly that a signaling pathway involving nodal, or nodal-related peptides, is an essential conserved element in mesoderm differentiation associated with vertebrate gastrulation and axial patterning.

Authors
Jones, CM; Kuehn, MR; Hogan, BL; Smith, JC; Wright, CV
MLA Citation
Jones, CM, Kuehn, MR, Hogan, BL, Smith, JC, and Wright, CV. "Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation." Development 121.11 (November 1995): 3651-3662.
PMID
8582278
Source
pubmed
Published In
Development (Cambridge)
Volume
121
Issue
11
Publish Date
1995
Start Page
3651
End Page
3662

Expression of bone morphogenetic protein-4 (BMP-4), bone morphogenetic protein-7 (BMP-7), fibroblast growth factor-8 (FGF-8) and sonic hedgehog (SHH) during branchial arch development in the chick.

Expression of Fgf-8, Bmp-4, Bmp-7, and shh in the branchial arches of the chick embryo is examined by in situ hybridization. Fgf-8 expression is initially broad and diffuse, becoming more tightly restricted, particularly in the epithelium of the posterior ectodermal margin (PEM) of the 2nd branchial arch. Bmp-7 transcripts, first seen at stage 12 in discrete regions corresponding to the developing branchial clefts, are later detected in both clefts and arches, including the PEM of the 2nd arch while Bmp-4 transcripts are detected at stage 18 in the distal tips of the arches. Shh expression remains localized, overlapping with both Bmp-7 and Fgf-8 in the PEM of the 2nd arch at stages 16 and 18. Based on these data, a model is proposed for the role of these signalling molecules in branchial arch development.

Authors
Wall, NA; Hogan, BL
MLA Citation
Wall, NA, and Hogan, BL. "Expression of bone morphogenetic protein-4 (BMP-4), bone morphogenetic protein-7 (BMP-7), fibroblast growth factor-8 (FGF-8) and sonic hedgehog (SHH) during branchial arch development in the chick." Mech Dev 53.3 (November 1995): 383-392.
PMID
8645604
Source
pubmed
Published In
Mechanisms of Development
Volume
53
Issue
3
Publish Date
1995
Start Page
383
End Page
392

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.

There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Authors
Ichiki, T; Labosky, PA; Shiota, C; Okuyama, S; Imagawa, Y; Fogo, A; Niimura, F; Ichikawa, I; Hogan, BL; Inagami, T
MLA Citation
Ichiki, T, Labosky, PA, Shiota, C, Okuyama, S, Imagawa, Y, Fogo, A, Niimura, F, Ichikawa, I, Hogan, BL, and Inagami, T. "Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor." Nature 377.6551 (October 26, 1995): 748-750.
PMID
7477267
Source
pubmed
Published In
Nature
Volume
377
Issue
6551
Publish Date
1995
Start Page
748
End Page
750
DOI
10.1038/377748a0

Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.

Bone morphogenetic protein-4 (BMP-4) is a member of the TGF-beta superfamily of polypeptide signaling molecules, closely related to BMP-2 and to Drosophila decapentaplegic (DPP). To elucidate the role of BMP-4 in mouse development the gene has been inactivated by homologous recombination in ES cells. Homozygous mutant Bmp-4tm1blh embryos die between 6.5 and 9.5 days p.c., with a variable phenotype. Most Bmp-4tm1blh embryos do not proceed beyond the egg cylinder stage, do not express the mesodermal marker T(Brachyury), and show little or no mesodermal differentiation. Some homozygous mutants develop to the head fold or beating heart/early somite stage or beyond. However, they are developmentally retarded and have truncated or disorganized posterior structures and a reduction in extraembryonic mesoderm, including blood islands. These results provide direct genetic evidence that BMP-4 is essential for several different processes in early mouse development, beginning with gastrulation and mesoderm formation. Moreover, in the presumed absence of zygotic ligand, it appears that homozygous mutants can be rescued partially by related proteins or by maternal BMP-4.

Authors
Winnier, G; Blessing, M; Labosky, PA; Hogan, BL
MLA Citation
Winnier, G, Blessing, M, Labosky, PA, and Hogan, BL. "Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse." Genes Dev 9.17 (September 1, 1995): 2105-2116.
PMID
7657163
Source
pubmed
Published In
Genes & development
Volume
9
Issue
17
Publish Date
1995
Start Page
2105
End Page
2116

Molecular morphogens. Upside-down ideas vindicated.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Molecular morphogens. Upside-down ideas vindicated." Nature 376.6537 (July 20, 1995): 210-211.
PMID
7617024
Source
pubmed
Published In
Nature
Volume
376
Issue
6537
Publish Date
1995
Start Page
210
End Page
211
DOI
10.1038/376210a0

Molecular and phenotypic characterization of a new mouse insertional mutation that causes a defect in the distal vertebrae of the spine.

We have identified and characterized the phenotype of a new insertional mutation in one line of transgenic mice. Mice carrying this mutation, which we have designated TgN(Imusd)370Rpw, display undulations of the vertebrae giving rise to a novel kinky-tail phenotype. Molecular characterization of the insertion site indicates that the transgene integration has occurred without any substantial alterations in the structure of the host sequences. Using probes that flank the insertion site, we have mapped the mutation to chromosome 5 near the semidominant mutation, thick tail (Tht). Thick tail does not complement the TgN(Imusd)370Rpw mutation; compound mutants containing one copy of each mutation display a more severe phenotype than either mutation individually.

Authors
Schrick, JJ; Dickinson, ME; Hogan, BL; Selby, PB; Woychik, RP
MLA Citation
Schrick, JJ, Dickinson, ME, Hogan, BL, Selby, PB, and Woychik, RP. "Molecular and phenotypic characterization of a new mouse insertional mutation that causes a defect in the distal vertebrae of the spine." Genetics 140.3 (July 1995): 1061-1067.
PMID
7672577
Source
pubmed
Published In
Genetics
Volume
140
Issue
3
Publish Date
1995
Start Page
1061
End Page
1067

Embryo research revisited.

Authors
Hogan, BL; Green, RM
MLA Citation
Hogan, BL, and Green, RM. "Embryo research revisited." Hastings Cent Rep 25.3 (May 1995): 2-6. (Letter)
PMID
7649740
Source
pubmed
Published In
The Hastings Center report
Volume
25
Issue
3
Publish Date
1995
Start Page
2
End Page
6

Colocalization of BMP 7 and BMP 2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development.

Members of the bone morphogenetic protein (BMP) class of transforming growth factor beta (TGF beta)-related molecules have been implicated in a variety of inductive processes throughout vertebrate development. The 60A subclass of BMPs contains at least four vertebrate members, BMPs 5-8. We have shown by library screening and in situ hybridization that of these four genes, BMP 7 is expressed earliest, in gastrulating embryos. Furthermore, BMP 7 transcripts are present at diverse sites throughout development, in a pattern consistent with a role in a variety of inductive interactions. Recent studies have shown that BMP 2/7 heterodimers have unique activities compared to the corresponding homodimers. For this reason, we compared the patterns of expression of BMP 2 and BMP 7 using in situ hybridization. Our results demonstrate that these BMPs are coexpressed in a number of tissues that are known to be the source of inductive signals, including the zone of polarizing activity and apical ectodermal ridge of the developing limb and the notochord, raising the possibility that BMP 2/7 heterodimers may mediate aspects of these tissue interactions. We also show that BMP 2 transcripts are restricted within the developing gut to dorsal endoderm, whereas sonic hedgehog has been localized to ventral and medial regions of the developing gut endoderm. These markers provide the first molecular evidence for dorsal/ventral polarity in the developing gut.

Authors
Lyons, KM; Hogan, BL; Robertson, EJ
MLA Citation
Lyons, KM, Hogan, BL, and Robertson, EJ. "Colocalization of BMP 7 and BMP 2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development." Mech Dev 50.1 (March 1995): 71-83.
PMID
7605753
Source
pubmed
Published In
Mechanisms of Development
Volume
50
Issue
1
Publish Date
1995
Start Page
71
End Page
83

Developmental expression of renal angiotensin II receptor genes in the mouse.

The cellular distribution of angiotensin II type 1 (AT1) and type 2 (AT2) receptor mRNA was examined in mouse kidneys at several embryonic stages (12 to 18 days; 19 days = full term) and up to three weeks after birth by in situ hybridization. The expression of both AT1 and AT2 mRNAs appeared simultaneously at 14 days of gestation. However, their distributions were contrasting: AT1 mRNA was expressed in mature glomeruli and maturing S-shaped bodies throughout the stages examined. AT1 expression was also detected at 16 days of gestation in the proximal and distal tubules and peaked at the end of gestation. Both the temporal and spatial expression of AT1 coincide with the differentiation and proliferation of glomerular mesangial and tubular cells during nephrogenesis. In contrast, AT2 mRNA was present only in the mesenchymal cells adjacent to the stalk of the ureter bud at early developmental stages, and, later, extended to the mesenchymal cells located near, but outside, the nephrogenic area of superficial cortex and also the cells between collecting ducts. AT2 expression in these regions decreased markedly within three weeks after birth. Temporally and spatially, AT2 mRNA expression coincides with the epithelial-mesenchymal interactions that take place during early phases of nephrogenesis. The site of AT2 expression also overlaps closely with that of a specific group of cells which undergo apoptosis following nephrogenesis. Thus, contrary to current belief, the activation of AT1 and AT2 genes takes place in different cell types of the kidney during embryonic development, and thereby conceivably contributes to the ontogeny of those specific renal cells.

Authors
Kakuchi, J; Ichiki, T; Kiyama, S; Hogan, BL; Fogo, A; Inagami, T; Ichikawa, I
MLA Citation
Kakuchi, J, Ichiki, T, Kiyama, S, Hogan, BL, Fogo, A, Inagami, T, and Ichikawa, I. "Developmental expression of renal angiotensin II receptor genes in the mouse." Kidney Int 47.1 (January 1995): 140-147.
PMID
7731139
Source
pubmed
Published In
Kidney international
Volume
47
Issue
1
Publish Date
1995
Start Page
140
End Page
147

Chemical skin carcinogenesis is prevented in mice by the induced expression of a TGF-beta related transgene.

Skin papillomas and squamous cell carcinomas (SCCs) are induced in mice by tumor initiation with a carcinogen followed by tumor promotion with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). These usually arise from preneoplastic lesions characterized by epidermal proliferation and hyperplasia, dermal edema, and inflammation. To evaluate the role of polypeptide growth factors in chemically induced skin carcinogenesis, we used transgenic mice carrying the cDNA for a TGF-beta related molecule, bone morphogenetic protein-4 (BMP-4), under the control of the regulatory elements of the cytokeratin IV* gene in a skin carcinogenesis protocol. Control non-transgenic littermates and BMP-4 transgenic mice were treated with a single dose of a carcinogen, N-methyl-N'-nitrosoguanidine (MNNG), and biweekly with the tumor promoter TPA for 9 months. In control littermates TPA induced epidermal hyperproliferation, atypia with "dark" cells, and dermal inflammation, resulting in papillomas and SCCs in 13 of 26 animals tested. In BMP-4 transgenic mice, TPA treatment induced the expression of the BMP-4 transgene in interfollicular epidermis but only minimal epidermal thickening, hyperproliferation, and inflammation were noted after the initial dose of TPA. Furthermore, the mitotic indices in transgenic epidermis after 9 months of TPA treatment were significantly lower than the corresponding indices from untreated transgenic epidermis. Consequently, none of the 22 transgenic animals tested developed papillomas or SCCs. In conclusion, we have shown that the TPA induced expression of the BMP-4 transgene blocks proliferation and inflammation in skin, steps that are critical to the subsequent formation of papillomas and SCCs and we characterized an inducible promotersystem which expresses polypeptides in interfollicular epidermis after exogenous stimulation.

Authors
Blessing, M; Nanney, LB; King, LE; Hogan, BL
MLA Citation
Blessing, M, Nanney, LB, King, LE, and Hogan, BL. "Chemical skin carcinogenesis is prevented in mice by the induced expression of a TGF-beta related transgene." Teratog Carcinog Mutagen 15.1 (1995): 11-21.
PMID
7604388
Source
pubmed
Published In
Teratogenesis, Carcinogenesis, and Mutagenesis
Volume
15
Issue
1
Publish Date
1995
Start Page
11
End Page
21

The TGF-β-related signalling system in mouse development

Secreted polypeptide signalling molecules of the TGF- superfamily play critical roles during mouse development. There are 20 known members of this diverse family in the mouse, including the TGF-s, inhibin/activins, BMPs, GDFs, and nodal. Mutations in genes for some of these ligands have been identified or created by targeted mutagenesis. A complex network of binding proteins, proteases, and receptors is involved in the processing, presentation and biological activity of TGF-β-related ligands. It is likely that variations in these modifying factors will explain how different genetic backgrounds can influence the severity and penetrance of mutant phenotypes. © 1995 Academic Press Ltd.

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "The TGF-β-related signalling system in mouse development." Seminars in Developmental Biology 6.4 (1995): 257-265.
Source
scival
Published In
Seminars in Developmental Biology
Volume
6
Issue
4
Publish Date
1995
Start Page
257
End Page
265
DOI
10.1016/S1044-5781(06)80051-4

Of bioethics and embryos

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "Of bioethics and embryos." Scientist 9.3 (1995).
Source
scival
Published In
Scientist (Philadelphia, Pa.)
Volume
9
Issue
3
Publish Date
1995

Upside-down ideas vindicated

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "Upside-down ideas vindicated." Nature 376.6537 (1995): 210-211.
Source
scival
Published In
Nature
Volume
376
Issue
6537
Publish Date
1995
Start Page
210
End Page
211

Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation

Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg(-/-)). Postnatally, Atg(-/-) animals show a modest delay in glomerular maturation. Although Atg(-/-) animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-β1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla.

Authors
Niimura, F; Labosky, PA; Kakuchi, J; Okubo, S; Yoshida, H; Oikawa, T; Ichiki, T; Naftilan, AJ; Fogo, A; Inagami, T; Hogan, BLM; Ichikawa, I
MLA Citation
Niimura, F, Labosky, PA, Kakuchi, J, Okubo, S, Yoshida, H, Oikawa, T, Ichiki, T, Naftilan, AJ, Fogo, A, Inagami, T, Hogan, BLM, and Ichikawa, I. "Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation." Journal of Clinical Investigation 96.6 (1995): 2947-2954.
PMID
8675666
Source
scival
Published In
Journal of Clinical Investigation
Volume
96
Issue
6
Publish Date
1995
Start Page
2947
End Page
2954
DOI
10.1172/JCI118366

Developmental signalling. Sorting out the signals.

New insights into the developmental roles played by the TGF-beta family of signalling molecules come from the identification in Drosophila of two transmembrane receptors encoded by the thick veins and saxophone genes.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Developmental signalling. Sorting out the signals." Curr Biol 4.12 (December 1, 1994): 1122-1124. (Review)
PMID
7704577
Source
pubmed
Published In
Current Biology
Volume
4
Issue
12
Publish Date
1994
Start Page
1122
End Page
1124

Mouse embryonic germ (EG) cell lines: transmission through the germline and differences in the methylation imprint of insulin-like growth factor 2 receptor (Igf2r) gene compared with embryonic stem (ES) cell lines.

Primordial germ cells of the mouse cultured on feeder layers with leukemia inhibitory factor, Steel factor and basic fibroblast growth factor give rise to cells that resemble undifferentiated blastocyst-derived embryonic stem cells. These primordial germ cell-derived embryonic germ cells can be induced to differentiate extensively in culture, form teratocarcinomas when injected into nude mice and contribute to chimeras when injected into host blastocysts. Here, we report the derivation of multiple embryonic germ cell lines from 8.5 days post coitum embryos of C57BL/6 inbred mice. Four independent embryonic germ cell lines with normal male karyotypes have formed chimeras when injected into BALB/c host blastocysts and two of these lines have transmitted coat color markers through the germline. We also show that pluripotent cell lines capable of forming teratocarcinomas and coat color chimeras can be established from primordial germ cells of 8.0 days p.c. embryos and 12.5 days p.c. genital ridges. We have examined the methylation status of the putative imprinting box of the insulin-like growth factor type 2 receptor gene (Igf2r) in these embryonic germ cell lines. No correlation was found between methylation pattern and germline competence. A significant difference was observed between embryonic stem cell and embryonic germ cell lines in their ability to maintain the methylation imprint of the Igf2r gene in culture. This may illustrate a fundamental difference between these two cell types.

Authors
Labosky, PA; Barlow, DP; Hogan, BL
MLA Citation
Labosky, PA, Barlow, DP, and Hogan, BL. "Mouse embryonic germ (EG) cell lines: transmission through the germline and differences in the methylation imprint of insulin-like growth factor 2 receptor (Igf2r) gene compared with embryonic stem (ES) cell lines." Development 120.11 (November 1994): 3197-3204.
PMID
7720562
Source
pubmed
Published In
Development (Cambridge)
Volume
120
Issue
11
Publish Date
1994
Start Page
3197
End Page
3204

TGF-beta related genes in development.

Embryonic induction is the process by which signals from one cell population change the developmental fate of another. Polypeptides related to growth factors are one group of molecules mediating many inductive events. Recent data on the embryonic expression and function of signaling proteins related to transforming growth factor beta, in both vertebrate and invertebrate systems, have shown that these molecules play important roles in both pattern formation and tissue specification during embryogenesis.

Authors
Wall, NA; Hogan, BL
MLA Citation
Wall, NA, and Hogan, BL. "TGF-beta related genes in development." Curr Opin Genet Dev 4.4 (August 1994): 517-522. (Review)
PMID
7950318
Source
pubmed
Published In
Current Opinion in Genetics & Development
Volume
4
Issue
4
Publish Date
1994
Start Page
517
End Page
522

Embryonic expression of mouse bone morphogenetic protein-1 (BMP-1), which is related to the Drosophila dorsoventral gene tolloid and encodes a putative astacin metalloendopeptidase.

cDNAs encoding a mouse gene closely related to human bone morphogenetic protein-1 (BMP-1) have been isolated from an 8.5-day p.c. embryo cDNA library. Analysis of the predicted amino acid sequence shows that the protein contains a putative zinc-binding astacin metalloendopeptidase domain, five Clr/s domains, and two potential Ca(2+)-binding EGF-like repeats. In overall domain organization it more closely resembles the Drosophila tolloid gene product than human BMP-1. By RNase protection, transcripts can be detected in the embryo at 6.5 days p.c. and persist at least until 16.5 days p.c. By in situ hybridization, transcripts are seen at high levels in the maternal deciduum and in the late-gastrulation stage embryo at low levels throughout the mesoderm. This low level of mesodermal expression continues through development but somewhat higher levels are seen in developing membranous and endochondral bone, in the submucosa of the intestine, the dermis of the skin, and the mesenchyme of the spleen and lung. High levels of BMP-1 transcripts are also seen from 9.5 days p.c. in the floorplate region of the developing neural tube. Potential therefore exists for the interaction of BMP-1 protein with products of TGF-beta-related genes expressed during embryogenesis.

Authors
Fukagawa, M; Suzuki, N; Hogan, BL; Jones, CM
MLA Citation
Fukagawa, M, Suzuki, N, Hogan, BL, and Jones, CM. "Embryonic expression of mouse bone morphogenetic protein-1 (BMP-1), which is related to the Drosophila dorsoventral gene tolloid and encodes a putative astacin metalloendopeptidase." Dev Biol 163.1 (May 1994): 175-183.
PMID
8174772
Source
pubmed
Published In
Developmental Biology
Volume
163
Issue
1
Publish Date
1994
Start Page
175
End Page
183
DOI
10.1006/dbio.1994.1133

Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-dimethylbenzanthracene.

A mouse mammary tumor virus enhancer/promoter-transforming growth factor alpha transgenic mouse model has been described in which mammary tumors develop (Y. Matsui et al., Cell, 61: 1147-1155, 1990). In Line 29, spontaneous mammary tumors do not develop before 300 days of age in virgin females. Herein, Line 29 virgin females and their nontransgenic littermates have been treated with 7,12-dimethylbenzanthracene (DMBA) at varying dosages and times. Orogastric instillation of a single dose of DMBA (0.5 mg) dramatically accelerates mammary tumor formation when administered to 21- and 56-day-old virgin transgenic females compared to their nontransgenic littermates. The latency period for tumor formation is significantly shorter in transgenic mice treated with DMBA at 56 days compared to transgenic mice treated with DMBA at 21 days when results are analyzed by time from DMBA administration. To determine whether differences in the proliferative state of the mammary gland may contribute to these findings, bromodeoxyuridine incorporation was examined in the mammary glands of untreated 21- and 56-day-old mice. No differences in bromodeoxyuridine incorporation were detected between 21-day-old transgenic and nontransgenic mice. However, there was a marked increase in bromodeoxyuridine incorporation in the epithelial cells comprising the smaller ducts of 56-day-old transgenic mice compared to their nontransgenic littermates. These data indicate an enhancing interaction between a growth factor and a genotoxic carcinogen in mammary tumorigenesis and provide evidence that the transforming growth factor alpha transgene acts as a tumor promoter in this experimental model.

Authors
Coffey, RJ; Meise, KS; Matsui, Y; Hogan, BL; Dempsey, PJ; Halter, SA
MLA Citation
Coffey, RJ, Meise, KS, Matsui, Y, Hogan, BL, Dempsey, PJ, and Halter, SA. "Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-dimethylbenzanthracene." Cancer Res 54.7 (April 1, 1994): 1678-1683.
PMID
8137281
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
7
Publish Date
1994
Start Page
1678
End Page
1683

On-line coupling of in vivo microdialysis sampling with capillary electrophoresis.

Microdialysis sampling has become an important means of continuously monitoring reactions in vivo. This sampling technique places a constraint on the analysis method because of the very small sample volume provided. On the other hand, microdialysis provides the advantage of clean samples that do not require cleanup prior to analysis. An on-line coupling of microdialysis sampling to capillary electrophoretic (CE) analysis is described that uses the advantages of microcolumn separations to overcome the small volume limitation. An interface was designed which converts the continuous microdialysis sample stream into discrete 60-nL sample plugs and then injects a portion of this plug into the CE system. The on-line interface provided precision of 2.6% with minimal band broadening or peak height loss relative to off-line sampling. Using a high-speed micellar electrokinetic chromatography (MEKC) separation, resolution of the investigational antineoplastic SR 4233 from its main metabolite SR 4317 was achieved in less than 60 s. This allowed the on-line system to achieve a 90-s temporal resolution for determining the pharmacokinetics of SR 4233 in vivo.

Authors
Hogan, BL; Lunte, SM; Stobaugh, JF; Lunte, CE
MLA Citation
Hogan, BL, Lunte, SM, Stobaugh, JF, and Lunte, CE. "On-line coupling of in vivo microdialysis sampling with capillary electrophoresis." Anal Chem 66.5 (March 1, 1994): 596-602.
PMID
8154588
Source
pubmed
Published In
Analytical Chemistry
Volume
66
Issue
5
Publish Date
1994
Start Page
596
End Page
602

HNF-3 beta as a regulator of floor plate development.

The transcription factor gene HNF-3 beta is expressed in the ventral midline of the mouse embryonic neural tube, including the floor plate, a structure important for dorsoventral patterning and axonal guidance. To assess HNF-3 beta function, the gene has been ectopically expressed in the midbrain/hindbrain of transgenic embryos using an En-2 promoter/enhancer. By 18.5 days postcoitum, transgenic brains show a range of abnormalities, including absent inferior colliculus and reduced cerebellum. Earlier, several genes normally expressed in the floor plate (BMP-1, Steel factor, and HNF-3 alpha) are induced within the same ectopic dorsal domain as HNF-3 beta, and autoactivation of the endogenous HNF-3 beta is observed. Conversely, expression of the dorsal gene Pax-3 is suppressed. Ectopic dorsal neuronal differentiation and abnormal dorsal axonal projections are also seen. These results suggest that HNF-3 beta is an important regulator of floor plate development in vivo.

Authors
Sasaki, H; Hogan, BL
MLA Citation
Sasaki, H, and Hogan, BL. "HNF-3 beta as a regulator of floor plate development." Cell 76.1 (January 14, 1994): 103-115.
PMID
8287471
Source
pubmed
Published In
Cell
Volume
76
Issue
1
Publish Date
1994
Start Page
103
End Page
115

Embryonic expression of Lim-1, the mouse homolog of Xenopus Xlim-1, suggests a role in lateral mesoderm differentiation and neurogenesis.

cDNAs encoded by the mouse homolog (Lim-1) of the Xenopus LIM-class homeobox gene Xlim-1 have been isolated from an 8.5-day mouse embryo cDNA library. Nucleotide and deduced amino acid sequences show a high degree of identity with Xlim-1 in the LIM and homeodomains, and 85% identity over the whole protein. An interspecific back-cross has been used to show close linkage of Lim-1 to the endogenous proviral marker Mpmv-4 on mouse chromosome 11. Whole mount in situ hybridization studies have been carried out on mouse embryos between 6.5 and 10.5 days. In mid- to late-streak stage embryos, Lim-1 is expressed in a restricted region of mesoderm in the primitive streak, with the highest level of signal at the anterior. At 7.5 days, transcripts can be seen in a horseshoe-shaped pattern in the periphery of the node, as well as along both sides of the immediately adjacent notochord. In addition, transcripts are present in presumptive lateral and intermediate mesoderm. Later, expression becomes progressively restricted to intermediate mesoderm, the nephrogenic cords, and eventually mesonephric ducts and tubules. By 10.5 days Lim-1 transcripts also appear in restricted regions of the central nervous system (CNS) that are associated with sensory function. The lateral diencephalon, hindbrain, and presumed commissural neurons in the dorsal spinal cord all show Lim-1 expression. In the adult, Lim-1 is expressed in the cerebellum/medulla and kidney, and at very low levels in the cerebrum. These data suggest that in the mouse embryo Lim-1 plays a role in early mesoderm formation and later specification of a differentiated phenotype in subsets of cells of the mesonephros and sensory neurons of the CNS.

Authors
Barnes, JD; Crosby, JL; Jones, CM; Wright, CV; Hogan, BL
MLA Citation
Barnes, JD, Crosby, JL, Jones, CM, Wright, CV, and Hogan, BL. "Embryonic expression of Lim-1, the mouse homolog of Xenopus Xlim-1, suggests a role in lateral mesoderm differentiation and neurogenesis." Dev Biol 161.1 (January 1994): 168-178.
PMID
7904966
Source
pubmed
Published In
Developmental Biology
Volume
161
Issue
1
Publish Date
1994
Start Page
168
End Page
178
DOI
10.1006/dbio.1994.1018

Growth factors in development: the role of TGF-beta related polypeptide signalling molecules in embryogenesis.

Embryonic induction, the process by which signals from one cell population influence the fate of another, plays an essential role in the development of all organisms so far studied. In many cases, the signalling molecules belong to large families of highly conserved proteins, originally identified as mammalian growth factors. The largest known family is related to Transforming Growth Factor-beta (TGF-beta) and currently consists of at least 24 different members. Genetic studies in Drosophila on the TGF-beta related gene, decapentaplegic (dpp), reveal the existence of conserved mechanisms regulating both the expression of the protein during development and the way in which it interacts with other signalling molecules to generate pattern within embryonic tissues. Comparative studies on another TGF-beta related gene, known as Bone Morphogenetic Protein-4 (BMP-4), in Xenopus and mouse point to a conserved role in specifying posteroventral mesoderm during gastrulation. Analysis of other polypeptide signalling molecules during gastrulation suggests that their interaction in the generation of the overall body plan has also been conserved during vertebrate evolution.

Authors
Hogan, BL; Blessing, M; Winnier, GE; Suzuki, N; Jones, CM
MLA Citation
Hogan, BL, Blessing, M, Winnier, GE, Suzuki, N, and Jones, CM. "Growth factors in development: the role of TGF-beta related polypeptide signalling molecules in embryogenesis." Dev Suppl (1994): 53-60. (Review)
PMID
7579524
Source
pubmed
Published In
Dev Suppl
Publish Date
1994
Start Page
53
End Page
60

Embryonic germ cell lines and their derivation from mouse primordial germ cells.

When primordial germ cells of the mouse are cultured on feeder layers with the addition of the polypeptide signalling molecules leukaemia inhibitory factor, Steel factor and basic fibroblast growth factor they give rise to cells that resemble undifferentiated blastocyst-derived embryonic stem cells. These primordial germ cell-derived embryonic germ cells (EG cells) can be induced to differentiate extensively in culture and also form teratocarcinomas when injected into nude mice. Additionally, they contribute to chimeras when injected into host blastocysts. We have derived multiple EG cell lines from 8.5 days post coitum (dpc) embryos of C57BL/6 inbred mice. Four independent EG cell lines with normal male karyotypes have formed chimeras (up to 70% coat colour chimerism) when injected into BALB/c host blastocysts. Chimeric mice from all four cell lines are fertile, but only those from one line have transmitted coat colour markers through the germline. Studies have also been carried out to determine whether gonadal primordial germ cells can give rise to pluripotent EG cells. Germ cells from gonads of 15.5 dpc C57BL/6 embryos and newborn mice failed to produce EG cell lines. EG cell lines capable of forming teratocarcinomas and coat colour chimeras have been established from primordial germ cells of 12.5 dpc genital ridges. We are currently testing the genomic imprinting status of the insulin-like growth factor type 2 receptor gene (Igf2r) in our different EG cell lines.

Authors
Labosky, PA; Barlow, DP; Hogan, BL
MLA Citation
Labosky, PA, Barlow, DP, and Hogan, BL. "Embryonic germ cell lines and their derivation from mouse primordial germ cells." Ciba Found Symp 182 (1994): 157-168. (Review)
PMID
7835148
Source
pubmed
Published In
Ciba Foundation symposium
Volume
182
Publish Date
1994
Start Page
157
End Page
168

Technology advancement for studying gene expression and gene function: A workshop report - National Institutes of Health

Authors
Nadeau, J; Wold, B; Bernstein, A; Davis, R; Helwig, U; Hogan, B; Housman, D; Klausner, R; Smithies, O; Graham, B
MLA Citation
Nadeau, J, Wold, B, Bernstein, A, Davis, R, Helwig, U, Hogan, B, Housman, D, Klausner, R, Smithies, O, and Graham, B. "Technology advancement for studying gene expression and gene function: A workshop report - National Institutes of Health." Mammalian Genome 5.3 (1994): 127-130.
PMID
8199399
Source
scival
Published In
Mammalian Genome
Volume
5
Issue
3
Publish Date
1994
Start Page
127
End Page
130

Growth factors in development: The role of TGF-β related polypeptide signalling molecules in embryogenesis

Embryonic induction, the process by which signals from one cell population influence the fate of another, plays an essential role in the development of all organisms so far studied. In many cases, the signalling molecules belong to large families of highly conserved proteins, originally identified as mammalian growth factors. The largest known family is related to Transforming Growth Factor-β (TGF-β) and currently consists of at least 24 different members. Genetic studies in Drosophila on the TGF-β related gene, decapentaplegic (dpp), reveal the existence of conserved mechanisms regulating both the expression of the protein during development and the way in which it interacts with other signalling molecules to generate pattern within embryonic tissues. Comparative studies on another TGF-β related gene, known as Bone Morphogenetic Protein-4 (BMP-4), in Xenopus and mouse point to a conserved role in specifying posteroventral mesoderm during gastrulation. Analysis of other polypeptide signalling molecules during gastrulation suggests that their interaction in the generation of the overall body plan has also been conserved during vertebrate evolution.

Authors
Hogan, BLM; Blessing, M; Winnier, GE; Suzuki, N; Jones, CM
MLA Citation
Hogan, BLM, Blessing, M, Winnier, GE, Suzuki, N, and Jones, CM. "Growth factors in development: The role of TGF-β related polypeptide signalling molecules in embryogenesis." Development 120.SUPPL. (1994): 53-60.
Source
scival
Published In
Development
Volume
120
Issue
SUPPL.
Publish Date
1994
Start Page
53
End Page
60

TGF-β related genes in development

Embryonic induction is the process by which signals from one cell population change the developmental fate of another. Polypeptides related to growth factors are one group of molecules mediating many inductive events. Recent data on the embryonic expression and function of signaling proteins related to transforming growth factor β, in both vertebrate and invertebrate systems, have shown that these molecules play important roles in both pattern formation and tissue specification during embryogenesis.

Authors
Wall, NA; Hogan, BLM
MLA Citation
Wall, NA, and Hogan, BLM. "TGF-β related genes in development." Current Opinion in Genetics and Development 4.4 (1994): 517-522.
Source
scival
Published In
Current Opinion in Genetics & Development
Volume
4
Issue
4
Publish Date
1994
Start Page
517
End Page
522
DOI
10.1016/0959-437X(94)90066-C

Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1.

The transforming growth factors beta (TGFs-beta) are potent inhibitors of cell proliferation and are usually secreted in a latent form. TGF-beta 1, TGF-beta 2, and TGF-beta 3 are expressed in distinct but overlapping patterns in the developing mouse mammary gland. To study the role of transforming growth factor-beta 1 (TGF-beta 1) in normal mammary development and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF-beta 1 s223/225 mutated to produce a constitutively active product under the control of the MMTV enhancer/promoter. Expression of the transgene, as confirmed by in situ hybridization, immunohistochemistry, and Northern blot analysis, was associated with marked suppression of the normal pattern of mammary ductal tree development in female transgenics. Reduction in total ductal tree volume was observed at 7 weeks, soon after estrous begins, and was most apparent at 13 weeks, as ductal growth in the normal mammary gland declines. This effect was seen in all three lines. However, during pregnancy, alveolar outgrowths developed from the hypoplastic ductal tree, and lactation occurred, therefore, all transgenic females could feed full litters. Unlike many other transgenic mouse models in which expression of growth factors or oncogenes under control of the MMTV promoter leads to mammary epithelial hyperplasia and increased tumor formation, the MMTV-TGF-beta 1S223/225 transgene causes conditional hypoplasia of the mammary ductal tree and no spontaneous tumors have been detected in the MMTV-TGF-beta 1S223/225 transgenic animals.

Authors
Pierce, DF; Johnson, MD; Matsui, Y; Robinson, SD; Gold, LI; Purchio, AF; Daniel, CW; Hogan, BL; Moses, HL
MLA Citation
Pierce, DF, Johnson, MD, Matsui, Y, Robinson, SD, Gold, LI, Purchio, AF, Daniel, CW, Hogan, BL, and Moses, HL. "Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1." Genes Dev 7.12A (December 1993): 2308-2317.
PMID
8253379
Source
pubmed
Published In
Genes & development
Volume
7
Issue
12A
Publish Date
1993
Start Page
2308
End Page
2317

Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo.

Four genes encoding fork-head-domain-containing proteins (FD genes) have been isolated from a mouse 8.5 days post coitum (p.c.) embryo cDNA library. Two are mouse homologues of rat HNF-3 beta and HNF-3 alpha. The other two are novel and have been named MF-1 and MF-2 (for mesoderm/mesenchyme fork head). Wholemount in situ hybridization of embryos between 6.5 and 9.5 days p. c. shows that each gene has a unique expression pattern. HNF-3 beta is expressed in the node, notochord, floor plate and gut, while HNF-3 alpha is mainly in the definitive endoderm and gut, but also in the floor plate of the midbrain. These results suggest that HNF-3 beta and HNF-3 alpha, in addition to their known functions as transcriptional activators in adult liver, play a role in body axis formation, neural tube patterning and definitive endoderm formation during gastrulation. MF-1 RNA is present in non-notochordal mesoderm, and in neural-crest-derived head mesenchyme, while MF-2 transcripts are found in the sclerotomes of the somites and in head mesenchyme, including that from neural crest. Studies on gastrulation stage embryos suggest that the early temporal and spatial patterns of HNF-3 beta, MF-1 and HNF-3 alpha correlate with populations of cells undergoing commitment to different developmental fates. A model is proposed linking FD gene expression with gastrulation events in the mouse.

Authors
Sasaki, H; Hogan, BL
MLA Citation
Sasaki, H, and Hogan, BL. "Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo." Development 118.1 (May 1993): 47-59.
PMID
8375339
Source
pubmed
Published In
Development (Cambridge)
Volume
118
Issue
1
Publish Date
1993
Start Page
47
End Page
59

Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation.

During gastrulation, the three germ layers of the embryo are formed and organized along the anterior-posterior body axis. In the mouse, gastrulation involves the delamination of ectodermal cells through the primitive streak and their differentiation into mesoderm. These processes do not occur in embryos homozygous for a retrovirally induced recessive prenatal lethal mutation, the strain 413-d insertional mutation. Instead of giving rise to mesoderm, embryonic ectoderm in 413-d mutants overproliferates and then rapidly degenerates, although extraembryonic lineages remain viable. Here we isolate a candidate for the mutated gene which encodes a new member of the transforming growth factor-beta (TGF-beta) superfamily. Expression is first detected in primitive streak-stage embryos at about the time of mesoderm formation. It then becomes highly localized in the node at the anterior of the primitive streak. This region is analogous to chick Hensen's node and Xenopus dorsal lip (Spemann's organizer), which can induce secondary body axes when grafted into host embryos (reviewed in refs 5 and 6). Our findings suggest that this gene, named nodal, encodes a signalling molecule essential for mesoderm formation and subsequent organization of axial structures in early mouse development.

Authors
Zhou, X; Sasaki, H; Lowe, L; Hogan, BL; Kuehn, MR
MLA Citation
Zhou, X, Sasaki, H, Lowe, L, Hogan, BL, and Kuehn, MR. "Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation." Nature 361.6412 (February 11, 1993): 543-547.
PMID
8429908
Source
pubmed
Published In
Nature
Volume
361
Issue
6412
Publish Date
1993
Start Page
543
End Page
547
DOI
10.1038/361543a0

Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles.

There is increasing evidence that members of the TGF-beta superfamily are important regulators of epithelial growth and differentiation in vivo. Here, transgenic mice have been used to study the role of the TGF-beta-related growth factors BMP-2 and BMP-4 in hair and whisker development. In the mature hair follicle, BMP-2 transcripts are normally seen only in precortex cells at the base of the hair shaft. In the transgenic mice reported here, BMP-4, a closely related molecule, has been ectopically expressed in the outer root sheath of hair and whisker follicles using an expression vector based on the bovine cytokeratin IV* promoter. In response to transgene expression, both outer root sheath cells below the stem cell compartment and hair matrix cells around the dermal papilla cease proliferation. In addition, the expression pattern of cytokeratin markers is disturbed in some transgenic hair follicles. These results support a model in which members of the TGF-beta superfamily play an active role in the inhibiton of cell proliferation and the onset of expression of trichocyte-specific genes that take place when cells leave the matrix of the follicle and differentiate into shaft cells.

Authors
Blessing, M; Nanney, LB; King, LE; Jones, CM; Hogan, BL
MLA Citation
Blessing, M, Nanney, LB, King, LE, Jones, CM, and Hogan, BL. "Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles." Genes Dev 7.2 (February 1993): 204-215.
PMID
8436293
Source
pubmed
Published In
Genes & development
Volume
7
Issue
2
Publish Date
1993
Start Page
204
End Page
215

Biosynthesis and in vivo localization of the decapentaplegic-Vg-related protein, DVR-6 (bone morphogenetic protein-6).

DVR-6 (BMP-6 or Vgr-1) is a member of the TGF-beta superfamily of polypeptide signaling molecules. In situ hybridization studies have previously shown that DVR-6 RNA is expressed in a variety of cell types in the mouse embryo, but no information has been available on protein localization and biosynthesis. We have produced a polyclonal antibody to the proregion of DVR-6 and used it to localize the protein in whole mount and sectioned embryonic, newborn, and adult mouse tissues. DVR-6 protein is expressed in the mouse nervous system beginning at 9.5 days postcoitum (d.p.c.) and continues through adulthood. A variety of epithelial tissues also produce DVR-6 protein, including the suprabasal layer of the skin, bronchiolar epithelium, and the cornea. Additionally, a stably transfected cell line, BMGE+H/D6c4, is used to study the biosynthesis of DVR-6 protein and evidence is presented for translational regulation of DVR-6 expression.

Authors
Wall, NA; Blessing, M; Wright, CV; Hogan, BL
MLA Citation
Wall, NA, Blessing, M, Wright, CV, and Hogan, BL. "Biosynthesis and in vivo localization of the decapentaplegic-Vg-related protein, DVR-6 (bone morphogenetic protein-6)." J Cell Biol 120.2 (January 1993): 493-502.
PMID
8421061
Source
pubmed
Published In
The Journal of Cell Biology
Volume
120
Issue
2
Publish Date
1993
Start Page
493
End Page
502

Inhibiting inhibin

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "Inhibiting inhibin." Current Biology 3.3 (1993): 170-172.
Source
scival
Published In
Current Biology
Volume
3
Issue
3
Publish Date
1993
Start Page
170
End Page
172
DOI
10.1016/0960-9822(93)90263-N

Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-β1

The transforming growth factors β (TGFs-β) are potent inhibitors of cell proliferation and are usually secreted in a latent form. TGF-β1, TGF-β2, and TGF-β3 are expressed in distinct but overlapping patterns in the developing mouse mammary gland. To study the role of transforming growth factor-β1 (TGF-β1) in normal mammary development and in mammary neoplasia, we have constructed three transgenic mouse lines that express a simian TGF- β1(S223/225) mutated to produce a constitutively active product under the control of the MMTV enhancer/promoter. Expression of the transgene, as confirmed by in situ hybridization, immunohistochemistry, and Northern blot analysis, was associated with marked suppression of the normal pattern of mammary ductal tree development in female transgenics. Reduction in total ductal tree volume was observed at 7 weeks, soon after estrous begins, and was most apparent at 13 weeks, as ductal growth in the normal mammary gland declines. This effect was seen in all three lines. However, during pregnancy, alveolar outgrowths developed from the hypoplastic ductal tree, and lactation occurred, therefore, all transgenic females could feed full litters. Unlike many other transgenic mouse models in which expression of growth factors or oncogenes under control of the MMTV promoter leads to mammary epithelial hyperplasia and increased tumor formation, the MMTV-TGF-β1(S223/225) transgene causes conditional hypoplasia of the mammary ductal tree and no spontaneous tumors have been detected in the MMTV-TGF-β1(S223/225) transgenic animals.

Authors
Jr, DFP; Johnson, MD; Matsui, Y; Robinson, SD; Gold, LI; Purchio, AF; Daniel, CW; Hogan, BLM; Moses, HL
MLA Citation
Jr, DFP, Johnson, MD, Matsui, Y, Robinson, SD, Gold, LI, Purchio, AF, Daniel, CW, Hogan, BLM, and Moses, HL. "Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-β1." Genes and Development 7.12 A (1993): 2308-2317.
Source
scival
Published In
Genes and Development
Volume
7
Issue
12 A
Publish Date
1993
Start Page
2308
End Page
2317

Determination of intracellular species at the level of a single erythrocyte via capillary electrophoresis with direct and indirect fluorescence detection.

Intracellular contents reflect the specific history of a cell including innate physiological heterogeneity as well as differing levels of exposure to environmental influences. A method capable of analyzing a variety of species from within a single human erythrocyte is demonstrated. Guided by a microscope, individual cells can be drawn into open capillaries of 10-microns i.d. On contact with a low ionic strength buffer solution, the cell lyses and releases its intracellular fluid. The ionic components are then separated by capillary electrophoresis. For glutathione, microderivatization with a fluorescent reagent can be accomplished in vitro with monobromobimane. The effects of extracellular oxidizing and reducing agents on the glutathione levels can thus be followed. For sodium and potassium, or any other ionic species, charge displacement of a fluorescent cation results in indirect fluorescence detection. The two detection modes are suitable for intracellular components present at low-attomole and sub-femtomole levels, respectively.

Authors
Hogan, BL; Yeung, ES
MLA Citation
Hogan, BL, and Yeung, ES. "Determination of intracellular species at the level of a single erythrocyte via capillary electrophoresis with direct and indirect fluorescence detection." Anal Chem 64.22 (November 15, 1992): 2841-2845.
PMID
1294009
Source
pubmed
Published In
Analytical Chemistry
Volume
64
Issue
22
Publish Date
1992
Start Page
2841
End Page
2845

Isolation of Vgr-2, a novel member of the transforming growth factor-beta-related gene family.

A cDNA clone, Vgr-2, with homology to certain members of the transforming growth factor-beta superfamily has been isolated from a mouse embryo cDNA library. The encoded protein shows significant similarity to members of the Vg-1/decapentaplegic/bone morphogenetic protein subgroup of the transforming growth factor-beta family. Within this group, Vgr-2 is more similar to Xenopus Vg-1 than to any other member so far isolated. The gene is expressed at highest levels during midgestation mouse development, and transcripts are localized by in situ hybridization to the osteogenic zone of developing bone. Vgr-2 is expressed in F9 teratocarcinoma cells, and its RNA levels are down-regulated within 24 h after differentiation with retinoic acid. The genomic organization of Vgr-2 and its location on mouse chromosome 6 are reported.

Authors
Jones, CM; Simon-Chazottes, D; Guenet, JL; Hogan, BL
MLA Citation
Jones, CM, Simon-Chazottes, D, Guenet, JL, and Hogan, BL. "Isolation of Vgr-2, a novel member of the transforming growth factor-beta-related gene family." Mol Endocrinol 6.11 (November 1992): 1961-1968.
PMID
1480182
Source
pubmed
Published In
Molecular endocrinology (Baltimore, Md.)
Volume
6
Issue
11
Publish Date
1992
Start Page
1961
End Page
1968
DOI
10.1210/mend.6.11.1480182

Evidence that Hensen's node is a site of retinoic acid synthesis.

Hensen's node of amniotes, like the Spemann organizer of amphibians, can induce a second body axis when grafted into a host embryo. The avian node, as well as several midline structures originating from it (notochord, floor plate), can also induce digit pattern duplications when grafted into the chick wing bud. We report here that the equivalent of Hensen's node from mouse is an effective inducer of digits in the chick wing bud. Tissues anterior and posterior to the node also evoke pattern duplications, but with a significantly lower efficiency. The finding that the murine node operates in an avian wing bud suggests that the same inducing agent(s) function in both primary and secondary embryonic fields and have been conserved during vertebrate evolution. Digit pattern duplications are also evoked by local administration of all-trans-retinoic acid. This similarity raises the possibility that Hensen's node is a source of retinoic acid. The mouse node is capable of synthesizing retinoic acid from its biosynthetic precursor all-trans-retinol at a substantially higher rate than either anterior or posterior tissues.

Authors
Hogan, BL; Thaller, C; Eichele, G
MLA Citation
Hogan, BL, Thaller, C, and Eichele, G. "Evidence that Hensen's node is a site of retinoic acid synthesis." Nature 359.6392 (September 17, 1992): 237-241.
PMID
1528265
Source
pubmed
Published In
Nature
Volume
359
Issue
6392
Publish Date
1992
Start Page
237
End Page
241
DOI
10.1038/359237a0

Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture.

Steel factor (SF) and LIF (leukemia inhibitory factor) synergistically promote the proliferation and survival of mouse primordial germ cells (PGCs), but only for a limited time period in culture. We show here that addition of bFGF to cultures in the presence of membrane-associated SF and LIF enhances the growth of PGCs and allows their continued proliferation beyond the time when they normally stop dividing in vivo. They form colonies of densely packed, alkaline phosphatase-positive, SSEA-1-positive cells resembling undifferentiated embryonic stem (ES) cells in morphology. These cultures can be maintained on feeder layers for at least 20 passages, and under appropriate conditions give rise to embryoid bodies and to multiple differentiated cell phenotypes in monolayer culture and in tumors in nude mice. PGC-derived ES cells can also contribute to chimeras when injected into host blastocysts. The long-term culture of PGCs and their reprogramming to pluripotential ES cells has important implications for germ cell biology and the induction of teratocarcinomas.

Authors
Matsui, Y; Zsebo, K; Hogan, BL
MLA Citation
Matsui, Y, Zsebo, K, and Hogan, BL. "Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture." Cell 70.5 (September 4, 1992): 841-847.
PMID
1381289
Source
pubmed
Published In
Cell
Volume
70
Issue
5
Publish Date
1992
Start Page
841
End Page
847

DVR-4 (bone morphogenetic protein-4) as a posterior-ventralizing factor in Xenopus mesoderm induction.

Establishment of mesodermal tissues in the amphibian body involves a series of inductive interactions probably elicited by a variety of peptide growth factors. Results reported here suggest that mesodermal patterning involves an array of signalling molecules including DVR-4, a TGF-beta-like molecule. We show that ectopic expression of DVR-4 causes embryos to develop with an overall posterior and/or ventral character, and that DVR-4 induces ventral types of mesoderm in animal cap explants. Moreover, DVR-4 overrides the dorsalizing effects of activin. DVR-4 is therefore the first molecule reported both to induce posteroventral mesoderm and to counteract dorsalizing signals such as activin. Possible interactions between these molecules resulting in establishment of the embryonic body plan are discussed.

Authors
Jones, CM; Lyons, KM; Lapan, PM; Wright, CV; Hogan, BL
MLA Citation
Jones, CM, Lyons, KM, Lapan, PM, Wright, CV, and Hogan, BL. "DVR-4 (bone morphogenetic protein-4) as a posterior-ventralizing factor in Xenopus mesoderm induction." Development 115.2 (June 1992): 639-647.
PMID
1425343
Source
pubmed
Published In
Development (Cambridge)
Volume
115
Issue
2
Publish Date
1992
Start Page
639
End Page
647

Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha. Characterization of mammary gland and skin proliferations.

Eight lines of transgenic mice expressing a mouse mammary tumor virus (MMTV) human transforming growth factor-alpha (TGF alpha) fusion gene were established. Three lines with distinctive phenotypes are presented. All have proliferative changes of the mammary gland. One line has sebaceous gland hyperplasia of the skin. Five histologic patterns of mammary gland hyperplasia based on two of these lines were identified: cystic hyperplasia, solid hyperplasia, dysplasia, adenoma, and adenocarcinoma. Human TGF alpha mRNA and protein were produced in all patterns but appeared reduced in solid hyperplasia, dysplasia, and adenocarcinoma. TGF alpha immunoreactivity in the mammary tissue, cystic fluid, and serum did not show significant differences; hyperplasia developed in 65% of multiparous mice and 45% of virgin mice by 12 months of age. Adenocarcinoma developed in 40% of multiparous mice and 30% of virgin mice by 16 months of age. These transgenic lines may provide useful models of mammary and sebaceous gland hyperplasia analogous to human disease.

Authors
Halter, SA; Dempsey, P; Matsui, Y; Stokes, MK; Graves-Deal, R; Hogan, BL; Coffey, RJ
MLA Citation
Halter, SA, Dempsey, P, Matsui, Y, Stokes, MK, Graves-Deal, R, Hogan, BL, and Coffey, RJ. "Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha. Characterization of mammary gland and skin proliferations." Am J Pathol 140.5 (May 1992): 1131-1146.
PMID
1316084
Source
pubmed
Published In
The American journal of pathology
Volume
140
Issue
5
Publish Date
1992
Start Page
1131
End Page
1146

Expression and modification of Hox 2.1 protein in mouse embryos.

A polyclonal antibody, alpha Hox 2.1a, has been generated and used to immunolocalize Hox 2.1 protein in mouse embryos. Protein is present in nuclei of all tissues previously shown to express Hox 2.1 RNA. In addition, protein is seen in somites and proximal regions of the limb buds, tissues in which Hox 2.1 RNA expression was not clearly detected previously by in situ hybridization. At the 7 somite stage, protein is detectable in the neural tube up to the level of somite 1, but later retracts to a more posterior position. Immunoblot, in vitro translation, and immunoprecipitation experiments were carried out to characterize the Hox 2.1 protein. The results show that the Hox 2.1 gene produces at least two related phosphorylated proteins present in different proportions in different tissues.

Authors
Wall, NA; Jones, CM; Hogan, BL; Wright, CV
MLA Citation
Wall, NA, Jones, CM, Hogan, BL, and Wright, CV. "Expression and modification of Hox 2.1 protein in mouse embryos." Mech Dev 37.3 (May 1992): 111-120.
PMID
1353982
Source
pubmed
Published In
Mechanisms of Development
Volume
37
Issue
3
Publish Date
1992
Start Page
111
End Page
120

Mouse Small eye results from mutations in a paired-like homeobox-containing gene.

Authors
Hill, RE; Favor, J; Hogan, BL; Ton, CC; Saunders, GF; Hanson, IM; Prosser, J; Jordan, T; Hastie, ND; van Heyningen, V
MLA Citation
Hill, RE, Favor, J, Hogan, BL, Ton, CC, Saunders, GF, Hanson, IM, Prosser, J, Jordan, T, Hastie, ND, and van Heyningen, V. "Mouse Small eye results from mutations in a paired-like homeobox-containing gene." Nature 355.6362 (February 20, 1992): 750-.
PMID
1346927
Source
pubmed
Published In
Nature
Volume
355
Issue
6362
Publish Date
1992
Start Page
750
DOI
10.1038/355750a0

Expression of TIMP in fetal and adult mouse tissues studied by in situ hybridization.

We have studied the expression of TIMP mRNA during mouse embryogenesis and in adult tissues using ribonuclease protection assays and in situ hybridization. Low levels of transcripts were found in many tissues, including embryonic kidney, amnion, lung and maternal deciduum and in these cases expression was not restricted to a phenotypically distinct sub-population of cells. In situ hybridization revealed high levels of TIMP transcripts in the corpus luteum of the adult ovary. Also, we observed significant expression in areas of membrane and endochondral bone formation in the embryo, commencing at about 15.5 d p.c. and increasing until birth. The pattern of TIMP expression in developing bone overlaps significantly with the localization of transforming growth factor beta (TGF beta) implying a role for this factor in the control of TIMP production in vivo.

Authors
Edwards, DR; Heath, JK; Hogan, BL; Nomura, S; Wills, AJ
MLA Citation
Edwards, DR, Heath, JK, Hogan, BL, Nomura, S, and Wills, AJ. "Expression of TIMP in fetal and adult mouse tissues studied by in situ hybridization." Matrix Suppl 1 (1992): 286-293.
PMID
1480039
Source
pubmed
Published In
Matrix (Stuttgart, Germany). Supplement
Volume
1
Publish Date
1992
Start Page
286
End Page
293

The TGF-beta-related DVR gene family in mammalian development.

The genes that encode the bone morphogenetic proteins and the Vg-related proteins are mammalian members of a group of TGF-beta-related genes, designated the DVR family, that includes the decapentaplegic gene of Drosophila and the Vg1 gene of Xenopus. Members of the DVR (decapentaplegic-Vg-related) family have been implicated in diverse processes during development, particularly in epithelial-mesenchymal interactions. The results of our in situ hybridization studies with postimplantation mouse embryos provide evidence for the involvement of DVR family members, particularly DVR-2, DVR-4 and DVR-6, in specific inductive interactions during the development of many organs, including the limb, the whisker follicle and the heart.

Authors
Lyons, KM; Jones, CM; Hogan, BL
MLA Citation
Lyons, KM, Jones, CM, and Hogan, BL. "The TGF-beta-related DVR gene family in mammalian development." Ciba Found Symp 165 (1992): 219-230. (Review)
PMID
1516470
Source
pubmed
Published In
Ciba Foundation symposium
Volume
165
Publish Date
1992
Start Page
219
End Page
230

Women in science [6]

Authors
Hogan, B
MLA Citation
Hogan, B. "Women in science [6]." Nature 360.6401 (1992): 204--.
PMID
1436103
Source
scival
Published In
Nature
Volume
360
Issue
6401
Publish Date
1992
Start Page
204-

Editorial overview

Authors
Williams, J; Hogan, B
MLA Citation
Williams, J, and Hogan, B. "Editorial overview." Current Opinion in Cell Biology 4.6 (1992): 919-922.
Source
scival
Published In
Current Opinion in Cell Biology
Volume
4
Issue
6
Publish Date
1992
Start Page
919
End Page
922

The making of the ear

Authors
Hogan, B; Wright, C
MLA Citation
Hogan, B, and Wright, C. "The making of the ear." Nature 355.6360 (1992): 494-495.
PMID
1346921
Source
scival
Published In
Nature
Volume
355
Issue
6360
Publish Date
1992
Start Page
494
End Page
495
DOI
10.1038/355494a0

Erratum: Mouse Small eye results from mutations in a paired-like homeobox-containing gene (Nature 354, 522-525 (1991))

Authors
Hill, RE; Favor, J; Hogan, BLM; Ton, CCT; Saunders, GF; Hanson, IM; Prosser, J; Jordan, T; Hastie, ND; Heyningen, VV
MLA Citation
Hill, RE, Favor, J, Hogan, BLM, Ton, CCT, Saunders, GF, Hanson, IM, Prosser, J, Jordan, T, Hastie, ND, and Heyningen, VV. "Erratum: Mouse Small eye results from mutations in a paired-like homeobox-containing gene (Nature 354, 522-525 (1991))." Nature 355.6362 (1992): 750--.
Source
scival
Published In
Nature
Volume
355
Issue
6362
Publish Date
1992
Start Page
750-
DOI
10.1038/355750a0

Expression of TGF-beta-related genes during mouse embryo whisker morphogenesis.

Authors
Jones, CM; Lyons, KM; Hogan, BL
MLA Citation
Jones, CM, Lyons, KM, and Hogan, BL. "Expression of TGF-beta-related genes during mouse embryo whisker morphogenesis." Ann N Y Acad Sci 642 (December 26, 1991): 339-344.
PMID
1809091
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
642
Publish Date
1991
Start Page
339
End Page
344

Mouse small eye results from mutations in a paired-like homeobox-containing gene.

Small eye (Sey) in mouse is a semidominant mutation which in the homozygous condition results in the complete lack of eyes and nasal primordia. On the basis of comparative mapping studies and on phenotypic similarities, Sey has been suggested to be homologous to congenital aniridia (lack of iris) in human. A candidate gene for the aniridia (AN) locus at 11p13 has been isolated by positional cloning and its sequence and that of the mouse homologue has been established (C.T., manuscript in preparation). This gene belongs to the paired-like class of developmental genes first described in Drosophila which contain two highly conserved motifs, the paired box and the homeobox. In vertebrates, genes which encode the single paired domain as well as those which express both motifs have been described as the Pax multigene family. A Pax gene recently described as Pax-6 is identical to the mouse homologue of the candidate aniridia gene. Here we report the analysis of three independent Sey alleles and show that indeed this gene is mutated and that the mutations would predictably interrupt gene function.

Authors
Hill, RE; Favor, J; Hogan, BL; Ton, CC; Saunders, GF; Hanson, IM; Prosser, J; Jordan, T; Hastie, ND; van Heyningen, V
MLA Citation
Hill, RE, Favor, J, Hogan, BL, Ton, CC, Saunders, GF, Hanson, IM, Prosser, J, Jordan, T, Hastie, ND, and van Heyningen, V. "Mouse small eye results from mutations in a paired-like homeobox-containing gene." Nature 354.6354 (December 19, 1991): 522-525.
PMID
1684639
Source
pubmed
Published In
Nature
Volume
354
Issue
6354
Publish Date
1991
Start Page
522
End Page
525
DOI
10.1038/354522a0

The DVR gene family in embryonic development.

The DVR gene family consists of at least 15 members, including decapentaplegic from Drosophila, Xenopus Vg1 and the mammalian bone morphogenetic protein genes, encoding secreted proteins closely related to transforming growth factor beta Genetic and biochemical evidence supports the idea that DVR proteins form part of a cascade of extracellular signalling molecules mediating inductive tissue interactions during development.

Authors
Lyons, KM; Jones, CM; Hogan, BL
MLA Citation
Lyons, KM, Jones, CM, and Hogan, BL. "The DVR gene family in embryonic development." Trends Genet 7.11-12 (November 1991): 408-412. (Review)
PMID
1820688
Source
pubmed
Published In
Trends in Genetics
Volume
7
Issue
11-12
Publish Date
1991
Start Page
408
End Page
412

The isolation and characterization of a novel cDNA demonstrating an altered mRNA level in nontumorigenic Wilms' microcell hybrid cells.

Wilms' tumor, a pediatric nephroblastoma, has been associated with genetic alterations of the 11p13 and 11p15 regions. The introduction of a der(11) chromosome into the G401 Wilms' tumor cell line has been shown previously to revert the tumorigenic phenotype. A subtractive cDNA/RNA hybridization performed between the tumorigenic parent (G401) and a nontumorigenic microcell hybrid of G401 (110.1/G401.1) containing the der(11) chromosome resulted in the identification of a single novel cDNA clone, designated QM. The cDNA is 745 nucleotides in length and encodes a predicted hydrophilic 25 kd basic protein, primarily consisting of alpha helices. The QM transcript is expressed in a wide variety of embryonic and adult tissues and demonstrates a down regulation of expression in adult kidney and heart. QM is also a member of a multigene family members of which map to chromosomes 6 and 14. The QM mRNA level is modulated between the tumorigenic and nontumorigenic cell lines and therefore may be involved in the maintenance of the nontumorigenic phenotype.

Authors
Dowdy, SF; Lai, KM; Weissman, BE; Matsui, Y; Hogan, BL; Stanbridge, EJ
MLA Citation
Dowdy, SF, Lai, KM, Weissman, BE, Matsui, Y, Hogan, BL, and Stanbridge, EJ. "The isolation and characterization of a novel cDNA demonstrating an altered mRNA level in nontumorigenic Wilms' microcell hybrid cells." Nucleic Acids Res 19.20 (October 25, 1991): 5763-5769.
PMID
1658743
Source
pubmed
Published In
Nucleic Acids Research
Volume
19
Issue
20
Publish Date
1991
Start Page
5763
End Page
5769

Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture.

Despite the importance of germ cells to the survival of species, surprisingly little is known about their embryological origin, proliferation, migration and entry into mitotic arrest or meiosis. Mutations in the murine Dominant White Spotting (W) and Steel genes, which respectively encode the c-kit tyrosine kinase receptor and the c-kit ligand (or Steel factor), impair the development of primordial germ cells (PGCs) in vivo, as well as haematopoietic stem cells and neural crest-derived melanoblasts. Here we use a monoclonal antibody against c-kit tyrosine kinase receptor and recombinant Steel factor to study the c-kit receptor-ligand system in cultured PGCs. In addition, we show that leukaemia inhibitory factor (also known as differentiation inhibitory activity), a factor secreted by STO fibroblasts, can stimulate proliferation of primordial germ cells in vitro.

Authors
Matsui, Y; Toksoz, D; Nishikawa, S; Nishikawa, S; Williams, D; Zsebo, K; Hogan, BL
MLA Citation
Matsui, Y, Toksoz, D, Nishikawa, S, Nishikawa, S, Williams, D, Zsebo, K, and Hogan, BL. "Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture." Nature 353.6346 (October 24, 1991): 750-752.
PMID
1719421
Source
pubmed
Published In
Nature
Volume
353
Issue
6346
Publish Date
1991
Start Page
750
End Page
752
DOI
10.1038/353750a0

Nucleotide sequence of mouse SCIP cDNA, a POU-domain transcription factor.

Authors
Zimmerman, EC; Jones, CM; Fet, V; Hogan, BL; Magnuson, MA
MLA Citation
Zimmerman, EC, Jones, CM, Fet, V, Hogan, BL, and Magnuson, MA. "Nucleotide sequence of mouse SCIP cDNA, a POU-domain transcription factor." Nucleic Acids Res 19.4 (February 25, 1991): 956-.
PMID
1840678
Source
pubmed
Published In
Nucleic Acids Research
Volume
19
Issue
4
Publish Date
1991
Start Page
956

Involvement of Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse.

Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 are members of the TGF-beta gene family most closely related to the Drosophila Decapentaplegic and Xenopus Vg-1 genes. Members of this gene family have been implicated in diverse processes during embryogenesis including epithelial-mesenchymal interactions. Here, we use in situ hybridization to localize BMP-4 and Vgr-1 transcripts during murine development. BMP-4 mRNA is found in a variety of tissues. In the 8.5 days p.c. embryo, transcripts are localized to the mesoderm posterior to the last somite. Later gestation embryos show expression in developing limbs, the embryonic heart, the facial processes and condensed mesenchymal cells associated with early whisker follicle formation. In the developing central nervous system (CNS), BMP-4 expression is restricted to the floor of the diencephalon associated with pituitary development. In contrast, Vgr-1 transcripts are found along the anteroposterior axis of the CNS, in cells immediately adjacent to the floor plate and in the roof plate extending to the forebrain. Together, the data support the hypothesis that polypeptide growth factors of the TGF-beta superfamily play key roles in the initial stages of neurogenesis and organogenesis during murine development.

Authors
Jones, CM; Lyons, KM; Hogan, BL
MLA Citation
Jones, CM, Lyons, KM, and Hogan, BL. "Involvement of Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse." Development 111.2 (February 1991): 531-542.
PMID
1893873
Source
pubmed
Published In
Development (Cambridge)
Volume
111
Issue
2
Publish Date
1991
Start Page
531
End Page
542

Editorial overview

Authors
Williams, J; Hogan, B
MLA Citation
Williams, J, and Hogan, B. "Editorial overview." Current Opinion in Cell Biology 3.6 (1991): 925-927.
Source
scival
Published In
Current Opinion in Cell Biology
Volume
3
Issue
6
Publish Date
1991
Start Page
925
End Page
927

Man's inhumanity [3]

Authors
Hogan, B
MLA Citation
Hogan, B. "Man's inhumanity [3]." Nature 349.6310 (1991): 558--.
PMID
2000128
Source
scival
Published In
Nature
Volume
349
Issue
6310
Publish Date
1991
Start Page
558-

Another hit for gene targeting

Authors
Wright, C; Hogan, B
MLA Citation
Wright, C, and Hogan, B. "Another hit for gene targeting." Nature 350.6318 (1991): 458-459.
PMID
1673019
Source
scival
Published In
Nature
Volume
350
Issue
6318
Publish Date
1991
Start Page
458
End Page
459
DOI
10.1038/350458a0

Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit.

Mice carrying mutations at the W (Dominant white spotting) and Sl (Steel) loci develop abnormalities in three independent systems: neural crest-derived melanocytes, primordial germ cells and haematopoietic stem cells. Consequently, homozygotes of viable mutant alleles have white coats and are sterile and severely anaemic. Tissue recombination studies predict that the W gene is expressed cell autonomously, whereas the product of the Sl locus affects the microenvironment in which the stem cells migrate, proliferate and differentiate. The W locus encodes the protoncogene c-kit, a member of the tyrosine kinase receptor family. The haematopoietic growth factor SCF (stem cell factor) has been identified as the product of the Sl locus and a ligand for c-kit. Here, we report that SCF is expressed during embryogenesis in cells associated with both the migratory pathways and homing sites of melanoblasts, germ cells and haematopoietic stem cells. Both SCF and c-kit are also expressed in a variety of other tissues, including the brain and spinal cord, suggesting that the receptor-ligand system has additional roles in embryogenesis.

Authors
Matsui, Y; Zsebo, KM; Hogan, BL
MLA Citation
Matsui, Y, Zsebo, KM, and Hogan, BL. "Embryonic expression of a haematopoietic growth factor encoded by the Sl locus and the ligand for c-kit." Nature 347.6294 (October 18, 1990): 667-669.
PMID
1699134
Source
pubmed
Published In
Nature
Volume
347
Issue
6294
Publish Date
1990
Start Page
667
End Page
669
DOI
10.1038/347667a0

Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation.

Transforming growth factor beta 1 (TGF beta 1) has been shown to have multiple effects on primary cultures of palate-derived cell types. We report the analysis, by in situ hybridization, of RNA expression for three different TGF beta isoforms (TGF beta 1, beta 2, and beta 3) during murine embryonic palate development. Differential expression of the three TGF beta genes is seen in the palatal shelves in mesenchymal and epithelial cells known to be involved in the morphogenesis of this organ. Taken together, these results suggest that the TGF beta s act as endogenous factors involved in the formation of the mammalian palate.

Authors
Pelton, RW; Hogan, BL; Miller, DA; Moses, HL
MLA Citation
Pelton, RW, Hogan, BL, Miller, DA, and Moses, HL. "Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation." Dev Biol 141.2 (October 1990): 456-460.
PMID
1698672
Source
pubmed
Published In
Developmental Biology
Volume
141
Issue
2
Publish Date
1990
Start Page
456
End Page
460

In situ hybridization analysis of TGF beta 3 RNA expression during mouse development: comparative studies with TGF beta 1 and beta 2.

To date, three closely-related TGF beta genes have been found in the mouse; TGF beta 1, TGF beta 2 and TGF beta 3. Previous experiments have indicated that TGF beta 1 and TGF beta 2 may play important roles during mouse embryogenesis. The present study now reports the distribution of transcripts of TGF beta 3 in comparison to the other two genes and reveals overlapping but distinct patterns of RNA expression. TGF beta 3 RNA is expressed in a diverse array of tissues including perichondrium, bone, intervertebral discs, mesenteries, pleura, heart, lung, palate, and amnion, as well as in central nervous system (CNS) structures such as the meninges, choroid plexus and the olfactory bulbs. Furthermore, in several organ systems, TGF beta 3 transcripts are expressed during periods of active morphogenesis suggesting that the protein may be an important factor for the growth and differentiation of many embryonic tissues.

Authors
Pelton, RW; Dickinson, ME; Moses, HL; Hogan, BL
MLA Citation
Pelton, RW, Dickinson, ME, Moses, HL, and Hogan, BL. "In situ hybridization analysis of TGF beta 3 RNA expression during mouse development: comparative studies with TGF beta 1 and beta 2." Development 110.2 (October 1990): 609-620.
PMID
1723948
Source
pubmed
Published In
Development (Cambridge)
Volume
110
Issue
2
Publish Date
1990
Start Page
609
End Page
620

Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2A (BMP-2A).

Bone morphogenetic protein-2A (BMP-2A) is a member of the transforming growth factor beta (TGF beta) gene family that has been implicated in cartilage and bone formation. Here we use in situ hybridization to show that BMP-2A RNA is expressed in a variety of embryonic epithelial and mesenchymal tissues outside of the developing skeletal system, including cell populations known to play important roles in morphogenesis. Thus, high levels of transcripts are found in developing limb buds (ventral ectoderm and apical ectodermal ridge), heart (myocardium of the atrioventricular canal), whisker follicles (ectodermal placodes, hair matrix and precortex cells), tooth buds (epithelial buds, dental papilla and odontoblasts), and craniofacial mesenchyme, as well as a number of other sites. The expression patterns of BMP-2A are different from those of TGF beta-1, -2 and -3, and this is illustrated in detail in the developing whisker follicles. These results suggest that BMP-2A plays multiple roles in morphogenesis and pattern formation in the vertebrate embryo.

Authors
Lyons, KM; Pelton, RW; Hogan, BL
MLA Citation
Lyons, KM, Pelton, RW, and Hogan, BL. "Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2A (BMP-2A)." Development 109.4 (August 1990): 833-844.
PMID
2226202
Source
pubmed
Published In
Development (Cambridge)
Volume
109
Issue
4
Publish Date
1990
Start Page
833
End Page
844

Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice.

To study the role of transforming growth factor alpha (TGF alpha) in normal mammary development and mammary neoplasia in vivo, we have generated transgenic mice in which a human TGF alpha cDNA is expressed under the control of the MMTV enhancer/promoter. Overexpression of TGF alpha in the mammary epithelium, as confirmed by in situ hybridization and immunohistochemistry, is associated with hyperplasia of alveoli and terminal ducts in virgin female and pregnant transgenic mice. A range of morphologic abnormalities including lobular hyperplasia, cystic hyperplasia, adenoma, and adenocarcinoma is seen in mammary tissue of transgenic females. In contrast, no morphologic abnormalities are seen in transgenic males in spite of TGF alpha overexpression in salivary glands and reproductive organs. TGF alpha can therefore act as an oncogene in vivo and appears to predispose mammary epithelium to neoplasia and carcinoma.

Authors
Matsui, Y; Halter, SA; Holt, JT; Hogan, BL; Coffey, RJ
MLA Citation
Matsui, Y, Halter, SA, Holt, JT, Hogan, BL, and Coffey, RJ. "Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice." Cell 61.6 (June 15, 1990): 1147-1155.
PMID
2161707
Source
pubmed
Published In
Cell
Volume
61
Issue
6
Publish Date
1990
Start Page
1147
End Page
1155

Location of the gene involving the small eye mutation on mouse chromosome 2 suggests homology with human aniridia 2 (AN2).

Using an interspecific backcross, we have mapped the gene involved in the mouse Small eye mutation (SeyMH) relative to six cloned markers on chromosome 2 (Hox-5.1, Cas-1, Fshb, Bmp-2a, and ld) and the agouti locus. The results suggest that the Sey gene maps between Fshb and Cas-1. Human mapping studies have shown that the aniridia (AN2) gene, which is part of the Wilms tumor susceptibility, aniridia, genitourinary abnormalities, and mental retardation (WAGR) complex, is also between FSHB and CAT on human chromosome 11. The conserved linkage of the cloned markers and the similarity of the Sey/+ and AN2/+ phenotypes suggest that the gene involved in the Sey mutation is the mouse homolog of the human AN2 gene.

Authors
van der Meer-de Jong, R; Dickinson, ME; Woychik, RP; Stubbs, L; Hetherington, C; Hogan, BL
MLA Citation
van der Meer-de Jong, R, Dickinson, ME, Woychik, RP, Stubbs, L, Hetherington, C, and Hogan, BL. "Location of the gene involving the small eye mutation on mouse chromosome 2 suggests homology with human aniridia 2 (AN2)." Genomics 7.2 (June 1990): 270-275.
PMID
2347591
Source
pubmed
Published In
Genomics
Volume
7
Issue
2
Publish Date
1990
Start Page
270
End Page
275

Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci.

Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the limb deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17). Additionally, a large interstitial segment of the 2(17) chromosome, immediately adjacent and proximal to the insertion site, did not match bands 2E4-2H1 at corresponding positions on a normal chromosome 2. Molecular analysis detected a DNA rearrangement in which a portion of the ld locus was joined to sequences normally tightly linked to the a locus. This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation, designated ldIn2 and ajIn2, were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.

Authors
Woychik, RP; Generoso, WM; Russell, LB; Cain, KT; Cacheiro, NL; Bultman, SJ; Selby, PB; Dickinson, ME; Hogan, BL; Rutledge, JC
MLA Citation
Woychik, RP, Generoso, WM, Russell, LB, Cain, KT, Cacheiro, NL, Bultman, SJ, Selby, PB, Dickinson, ME, Hogan, BL, and Rutledge, JC. "Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci." Proc Natl Acad Sci U S A 87.7 (April 1990): 2588-2592.
PMID
2320577
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
87
Issue
7
Publish Date
1990
Start Page
2588
End Page
2592

Indirect fluorometric detection of tryptic digests separated by capillary zone electrophoresis.

This work demonstrates the analytical utility of indirect fluorescence detection with capillary zone electrophoresis (CZE) for the analysis of trace quantities of macromolecular mixtures. Detection is based upon charge displacement and is not based upon any absorption or emission property of the analyte. No derivatization step is required. Indirect fluorescence is therefore a general detector for electrophoresis. Subfemtomolar quantities of tryptic digest mixtures are separated within three minutes, and reproducible peaks are obtained from the mixtures. Mass limits of detection are 3000 times lower than those of commercial high-performance liquid chromatography (HPLC) UV absorbance detectors and 180 times lower than those of UV absorbance detectors in CZE systems. This separation and detection system should be well suited to analysis of trace quantities of mixtures of peptides.

Authors
Hogan, BL; Yeung, ES
MLA Citation
Hogan, BL, and Yeung, ES. "Indirect fluorometric detection of tryptic digests separated by capillary zone electrophoresis." J Chromatogr Sci 28.1 (January 1990): 15-18.
PMID
2295690
Source
pubmed
Published In
Journal of chromatographic science
Volume
28
Issue
1
Publish Date
1990
Start Page
15
End Page
18

Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development.

Although specific details may vary from system to system, some general concepts have emerged from studies of the regulation of ECM components, proteases, and protease inhibitors by growth factors. Growth factors may be divided into those that enhance matrix synthesis and inhibit matrix degradation and those that stimulate protease production and result in a general degradation of ECM. These relationships are illustrated in Fig. 3. In general, growth factors such as EGF, PDGF, bFGF, and IL-1 induce genes for ECM-degrading proteinases and their activators (e.g., metalloproteinases and PAs). This concerted release of proteases results in the degradation of the many components of basement membranes or ECM. Other growth factors (e.g., the TGF-beta family) stimulate the synthesis of ECM structural proteins (e.g., collagens and fibronectin), elevate levels of inhibitors of proteases (e.g., TIMP and PAI-1), and repress expression of the matrix-degrading metalloproteinases and PA. The overall result is systems in which such a relationship seems very likely. Direct evidence should become available within the next few years now that the technology exists to correlate spatial and temporal expression of growth factors with expression of ECM-associated proteases and inhibitors and to misregulate this expression in specific ways, for example, in transgenic mice. Future studies involving the use of model systems in which complex tissue interactions and organogenesis can be followed in culture should also provide the opportunity to examine cause-and-effect relationships between growth factors and ECM-modulating proteins.

Authors
Matrisian, LM; Hogan, BL
MLA Citation
Matrisian, LM, and Hogan, BL. "Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development." Curr Top Dev Biol 24 (1990): 219-259. (Review)
PMID
2199157
Source
pubmed
Published In
Current topics in developmental biology
Volume
24
Publish Date
1990
Start Page
219
End Page
259

Developmental regulation of mouse SPARC (osteonectin) gene expression.

Authors
Nomura, S; Hashmi, S; Hogan, BL
MLA Citation
Nomura, S, Hashmi, S, and Hogan, BL. "Developmental regulation of mouse SPARC (osteonectin) gene expression." Ann N Y Acad Sci 580 (1990): 252-259.
PMID
2337300
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
580
Publish Date
1990
Start Page
252
End Page
259

The HOX-5 and surfeit gene clusters are linked in the proximal portion of mouse chromosome 2

Using an interspecies backcross, we have mapped the HOX-5 and surfeit (surf) gene clusters within the proximal portion of mouse chromosome 2. While the HOX-5 cluster of homeobox-containing genes has been localized to chromosome 2, bands C3-E1, by in situ hybridization, its more precise position relative to the genes and cloned markers of chromosome 2 was not known. Surfeit, a tight cluster of at least six highly conserved "housekeeping" genes, has not been previously mapped in mouse, but has been localized to human chromosome 9q, a region of the human genome with strong homology to proximal mouse chromosome 2. The data presented here place HOX-5 in the vicinity of the closely linked set of developmental mutations rachiterata, lethargic, and fidget and place surf close to the proto-oncogene Abl, near the centromere of chromosome 2. © 1990.

Authors
Stubbs, L; Huxley, C; Hogan, B; Evans, T; Fried, M; Duboule, D; Lehrach, H
MLA Citation
Stubbs, L, Huxley, C, Hogan, B, Evans, T, Fried, M, Duboule, D, and Lehrach, H. "The HOX-5 and surfeit gene clusters are linked in the proximal portion of mouse chromosome 2." Genomics 6.4 (1990): 645-650.
PMID
1971250
Source
scival
Published In
Genomics
Volume
6
Issue
4
Publish Date
1990
Start Page
645
End Page
650
DOI
10.1016/0888-7543(90)90499-K

Chromosomal localization of seven members of the murine TGF-β superfamily suggests close linkage to several morphogenetic mutant loci

Chromosomal locations have been assigned to seven members of the TGF-β superfamily using an interspecific mouse backcross. Probes for the Tgfb-1, -2, and -3, Bmp-2a and -3, and Vgr-1 genes recognized only single loci, whereas the Bmp-2b probe recognized two independently segregating loci (designated Bmp-2b1 and Bmp-2b2). The results show that the seven members of the TGF-β superfamily map to eight different chromosomes, indicating that the TGF-β family has become widely dispersed during evolution. Five of the eight loci (Tgfb-1, Bmp-2a, Bmp-2b1, Bmp-2b2, Vgr-1) mapped near mutant loci associated with connective tissue and skeletal disorders, raising the possibility that at least some of these mutations result from defects in TGF-β-related genes. © 1990.

Authors
Dickinson, ME; Kobrin, MS; Silan, CM; Kingsley, DM; Justice, MJ; Miller, DA; Ceci, JD; Lock, LF; Lee, A; Buchberg, AM; Siracusa, LD; Lyons, KM; Derynck, R; Hogan, BLM; Copeland, NG; Jenkins, NA
MLA Citation
Dickinson, ME, Kobrin, MS, Silan, CM, Kingsley, DM, Justice, MJ, Miller, DA, Ceci, JD, Lock, LF, Lee, A, Buchberg, AM, Siracusa, LD, Lyons, KM, Derynck, R, Hogan, BLM, Copeland, NG, and Jenkins, NA. "Chromosomal localization of seven members of the murine TGF-β superfamily suggests close linkage to several morphogenetic mutant loci." Genomics 6.3 (1990): 505-520.
PMID
1970330
Source
scival
Published In
Genomics
Volume
6
Issue
3
Publish Date
1990
Start Page
505
End Page
520
DOI
10.1016/0888-7543(90)90480-I

Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development.

Although specific details may vary from system to system, some general concepts have emerged from studies of the regulation of ECM components, proteases, and protease inhibitors by growth factors. Growth factors may be divided into those that enhance matrix synthesis and inhibit matrix degradation and those that stimulate protease production and result in a general degradation of ECM. These relationships are illustrated in Fig. 3. In general, growth factors such as EGF, PDGF, bFGF, and IL-1 induce genes for ECM-degrading proteinases and their activators (e.g., metalloproteinases and PAs). This concerted release of proteases results in the degradation of the many components of basement membranes or ECM. Other growth factors (e.g., the TGF-beta family) stimulate the synthesis of ECM structural proteins (e.g., collagens and fibronectin), elevate levels of inhibitors of proteases (e.g., TIMP and PAI-1), and repress expression of the matrix-degrading metalloproteinases and PA. The overall result is systems in which such a relationship seems very likely. Direct evidence should become available within the next few years now that the technology exists to correlate spatial and temporal expression of growth factors with expression of ECM-associated proteases and inhibitors and to misregulate this expression in specific ways, for example, in transgenic mice. Future studies involving the use of model systems in which complex tissue interactions and organogenesis can be followed in culture should also provide the opportunity to examine cause-and-effect relationships between growth factors and ECM-modulating proteins.

Authors
Matrisian, LM; Hogan, BL
MLA Citation
Matrisian, LM, and Hogan, BL. "Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development." Current topics in developmental biology 24 (1990): 219-259.
Source
scival
Published In
Current topics in developmental biology
Volume
24
Publish Date
1990
Start Page
219
End Page
259
DOI
10.1016/S0070-2153(08)60089-7

Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development.

The murine Vgr-1 (Vg-related) and BMP-2a (bone morphogenetic protein 2a) genes are members of the decapentaplegic subgroup of the transforming growth factor-beta (TGF beta) superfamily. Although genetic and biochemical studies suggest that the members of this subgroup play important roles in development, little is known about their function in mammals. Therefore, we investigated the expression of Vgr-1 and BMP-2a RNAs in embryonic, newborn, and adult tissues by in situ hybridization. Vgr-1 RNA is maternally encoded in ovarian oocytes but declines in fertilized eggs and is undectable by the two- to four-cell stage. Only low levels of transcripts are seen in blastocysts and early postimplantation stages. From mid-gestation on, Vgr-1 RNA is expressed at high levels in developing skin, especially in the suprabasal cells of the proliferating epidermis but not in the dermis or hair follicles, both of which contain TGF beta 1 and/or TGF beta 2 RNAs. In contrast, BMP-2a transcripts are seen only in the hair follicles in the cells of the hair bulb cortex. Temporally and spatially distinct patterns of BMP-2a, Vgr-1, TGF beta 1, and TGF beta 2 expression are also seen in different populations of mesenchymal cells in the developing skeletal system (cartilage and bone). Our results suggest that the coordinated expression of several members of the TGF beta superfamily is required to control the progression of specific cell types through their differentiation pathways.

Authors
Lyons, KM; Pelton, RW; Hogan, BL
MLA Citation
Lyons, KM, Pelton, RW, and Hogan, BL. "Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development." Genes Dev 3.11 (November 1989): 1657-1668.
PMID
2481605
Source
pubmed
Published In
Genes & development
Volume
3
Issue
11
Publish Date
1989
Start Page
1657
End Page
1668

Distribution of expression of 2AR (osteopontin) in the embryonic mouse inner ear revealed by in situ hybridisation.

Using in situ hybridisation we have determined the distribution of expression of 2ar (also known as osteopontin, bone sialoprotein 1 or 44-kDa bone phosphoprotein) in the developing mouse inner ear. We have identified several discrete sites, both osteogenic and non-osteogenic, that express 2ar from embryonic day 16.5 (E16.5). In addition to the regions of developing bone of the calvaria and temporal bone, we have found 2ar expression in the epithelium of the sensory maculae (but not in the organ of Corti), in the vestibular and auditory ganglia and nerves (but not in the nerves that innervate the whiskers in the snout), in the epithelium that lines the endolymphatic sac (but not in the neighbouring and contiguous endolymphatic duct) and also in the epithelium that lines the semicircular canals. We found also individual cells scattered throughout the brain, loose mesenchyme and blood vessels of the head that were expressing 2ar. Several of the sites in the inner ear, for example the maculae and the endolymphatic sac, are known to be involved in the production of calcified matrix. The results extend the range of tissue types known to express the protein and demonstrate that tissues of histologically similar appearance can nonetheless differ in their gene expression.

Authors
Swanson, GJ; Nomura, S; Hogan, BL
MLA Citation
Swanson, GJ, Nomura, S, and Hogan, BL. "Distribution of expression of 2AR (osteopontin) in the embryonic mouse inner ear revealed by in situ hybridisation." Hear Res 41.2-3 (September 1989): 169-177.
PMID
2808147
Source
pubmed
Published In
Hearing Research
Volume
41
Issue
2-3
Publish Date
1989
Start Page
169
End Page
177

Localization of the mouse gene for secreted phosphoprotein 1 (Spp-1) (2ar, osteopontin, bone sialoprotein 1, 44-kDa bone phosphoprotein, tumor-secreted phosphoprotein) to chromosome 5, closely linked to Ric (Rickettsia resistance).

We have used a cDNA probe for mouse secreted phosphoprotein 1 (Spp-1, also known as 2ar, osteopontin, bone sialoprotein 1, 44-kDa bone phosphotein, tumor-secreted protein) to find a restriction fragment length polymorphism in the gene from C57BL/6J and DBA/2J mice. The strain distribution pattern in 25 BXD recombinant inbred lines is identical with that previously determined for the dominant, autosomal gene, Ricr (Rickettsia resistance). This places Spp-1 on mouse chromosome 5 with a 95% confidence limit of being within 4.32 cM of Ric. Evidence supporting the possibility of allelism between Spp-1 and Ric is briefly discussed.

Authors
Fet, V; Dickinson, ME; Hogan, BL
MLA Citation
Fet, V, Dickinson, ME, and Hogan, BL. "Localization of the mouse gene for secreted phosphoprotein 1 (Spp-1) (2ar, osteopontin, bone sialoprotein 1, 44-kDa bone phosphoprotein, tumor-secreted phosphoprotein) to chromosome 5, closely linked to Ric (Rickettsia resistance)." Genomics 5.2 (August 1989): 375-377.
PMID
2571582
Source
pubmed
Published In
Genomics
Volume
5
Issue
2
Publish Date
1989
Start Page
375
End Page
377

Expression of transforming growth factor beta 2 RNA during murine embryogenesis.

We have studied the temporal and spatial expression of transforming growth factor beta 2 (TGF beta 2) RNA in mouse embryos from 10.5 days post coitum (p.c.) to 3 days post partum (p.p.) by in situ hybridization analysis. TGF beta 2 RNA is expressed in a variety of tissues including bone, cartilage, tendon, gut, blood vessels, skin and fetal placenta, and is in general found in the mesenchymal component of these tissues. The expression of TGF beta 2 RNA changes during development in a manner consistent with a role for the gene product in mediating mesenchymal-epithelial interactions.

Authors
Pelton, RW; Nomura, S; Moses, HL; Hogan, BL
MLA Citation
Pelton, RW, Nomura, S, Moses, HL, and Hogan, BL. "Expression of transforming growth factor beta 2 RNA during murine embryogenesis." Development 106.4 (August 1989): 759-767.
PMID
2485246
Source
pubmed
Published In
Development (Cambridge)
Volume
106
Issue
4
Publish Date
1989
Start Page
759
End Page
767

Evidence for positive and negative regulatory elements in the 5'-flanking sequence of the mouse sparc (osteonectin) gene.

We have investigated the role of 5'-flanking DNA sequences in regulating the expression of the murine Sparc (osteonectin) gene in parietal endoderm cells and in F9 embryonal carcinoma cells induced to differentiate into parietal endoderm with retinoic acid and cyclic AMP. Varying lengths of flanking sequences extending up to 3.0 kilobase pairs 5' of the transcription initiation site were linked to the bacterial chloramphenicol transacetylase gene in the Bluescript M13- vector. The constructs were tested in transient assays, using a beta-galactosidase plasmid as a transfection control. Sequences between 78 and 169 base pairs upstream of the cap site are the minimum required for cell-type specific promoter activity; this region is dominated by two oligopurine/oligopyrimidine stretches or "GAGA" boxes and is highly conserved between the mouse and bovine genes. Addition of the sequence between -169 and -449, which includes part or all of a third GAGA box, results in increased parietal endoderm specific transcription, up to a maximum of 6.3-fold higher than in undifferentiated F9 cells. Further addition of sequences between -449 and -638 markedly reduces promoter activity in both cell types but parietal endoderm-specific activity is restored in constructs containing 2.2 and 3.0 kilobase pairs of flanking DNA. In addition, we have identified sequences related to the consensus sequence for steroid response elements, one of which is able to confer progesterone-enhanced transcription when tested with a heterologous promoter in steroid responsive cells. These results suggest that negative and positive elements normally interact to regulate the temporal and tissue-specific patterns of Sparc gene transcription seen in vivo.

Authors
Nomura, S; Hashmi, S; McVey, JH; Ham, J; Parker, M; Hogan, BL
MLA Citation
Nomura, S, Hashmi, S, McVey, JH, Ham, J, Parker, M, and Hogan, BL. "Evidence for positive and negative regulatory elements in the 5'-flanking sequence of the mouse sparc (osteonectin) gene." J Biol Chem 264.21 (July 25, 1989): 12201-12207.
PMID
2745436
Source
pubmed
Published In
The Journal of biological chemistry
Volume
264
Issue
21
Publish Date
1989
Start Page
12201
End Page
12207

Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the transforming growth factor beta gene superfamily.

The transforming growth factor beta (TGF-beta)-related products of the Xenopus Vg-1 and Drosophila decapentaplegic (DPP) genes have been implicated in the control of growth and differentiation during embryogenesis. We have isolated a mouse cDNA, Vgr-1, that encodes a polypeptide structurally related to Xenopus Vg-1. Sequence comparisons indicate that the Vgr-1 protein belongs to a family of DPP-like gene products within the TGF-beta superfamily. The levels of Vgr-1 RNA were determined in embryos and tissues isolated at various stages of development. A 3.5-kilobase mRNA increases throughout development and into adulthood in many tissues and in F9 teratocarcinoma cells differentiating into endoderm in response to retinoic acid and cAMP. The amino acid homologies and patterns of expression suggest that, like the DPP gene product, Vgr-1 plays a role at various stages of development.

Authors
Lyons, K; Graycar, JL; Lee, A; Hashmi, S; Lindquist, PB; Chen, EY; Hogan, BL; Derynck, R
MLA Citation
Lyons, K, Graycar, JL, Lee, A, Hashmi, S, Lindquist, PB, Chen, EY, Hogan, BL, and Derynck, R. "Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the transforming growth factor beta gene superfamily." Proc Natl Acad Sci U S A 86.12 (June 1989): 4554-4558.
PMID
2734307
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
86
Issue
12
Publish Date
1989
Start Page
4554
End Page
4558

Developmental expression of tissue inhibitor of metalloproteinase (TIMP) RNA.

Single-stranded antisense RNA probes have been used to study the expression of the metalloproteinase inhibitor TIMP (tissue inhibitor of metalloproteinases), during mouse embryogenesis and in adult tissues. Using a sensitive RNase protection assay, low levels of transcript can be detected in a variety of tissues, including maternal deciduum, embryonic kidney, lung and amnion. Higher levels are seen in osteogenic tissues such as calvaria, while the highest level in any tissue is found in the ovary, though even here expression is an order of magnitude below that observed in growth factor-treated fibroblasts in vitro. Using the technique of in situ hybridization, TIMP transcripts can first be detected in osteogenic tissues in the head and limb at about 15.5 days post coitum, and increase in amount until birth. The high levels of TIMP RNA in the ovary are localized to cells of the corpora lutea.

Authors
Nomura, S; Hogan, BL; Wills, AJ; Heath, JK; Edwards, DR
MLA Citation
Nomura, S, Hogan, BL, Wills, AJ, Heath, JK, and Edwards, DR. "Developmental expression of tissue inhibitor of metalloproteinase (TIMP) RNA." Development 105.3 (March 1989): 575-583.
PMID
2693036
Source
pubmed
Published In
Development (Cambridge)
Volume
105
Issue
3
Publish Date
1989
Start Page
575
End Page
583

Expression of genes for non-collagenous proteins during embryonic bone formation.

In situ hybridization has been used to localize RNAs for a variety of non-collagenous proteins during embryogenesis of the mouse, with particular reference to bone formation. Transcripts of the Sparc (osteonectin) gene are first detected around 14.5d post coitum (p.c.) in the periosteal layer around the cartilage model of long bones and in membrane bone in the head. By 15.5d p.c. transcripts are seen in hypertrophic cartilage and later in cells within the bone closely associated with new matrix. By contrast, RNA for 2ar (osteopontin) is not seen in the periosteal layer but is confined to cells in the marrow region. TIMP (tissue inhibitor of metalloproteinase) transcripts show a very similar distribution to those for Sparc.

Authors
Nomura, S; Wills, AJ; Edwards, DR; Heath, JK; Hogan, BL
MLA Citation
Nomura, S, Wills, AJ, Edwards, DR, Heath, JK, and Hogan, BL. "Expression of genes for non-collagenous proteins during embryonic bone formation." Connect Tissue Res 21.1-4 (1989): 31-35. (Review)
PMID
2691198
Source
pubmed
Published In
Connective Tissue Research (Informa)
Volume
21
Issue
1-4
Publish Date
1989
Start Page
31
End Page
35

Expression of the homeobox gene, Hox 2.1, during mouse embryogenesis.

This article reviews recent studies on the expression of the homeobox gene, Hox 2.1, during mouse embryogenesis, using the technique of in situ hybridization. Differential hybridization of radiolabelled antisense versus sense strand RNA is first clearly detected in sections of 8.5 day post coitum (p.c.) early somite embryos. At 12.5 days p.c., higher levels of Hox 2.1 expression are seen in the spinal cord, extending into the base of the hind brain. Hybridization of antisense Hox 2.1 RNA is also seen in the spinal ganglia, in the nodose ganglia of the Xth cranial nerve (which contains derivatives of the neural crest arising from the posterior hind brain), and in the myenteric plexus. Mesodermal cells of certain visceral organs also express Hox 2.1 RNA, in particular the mesoderm of the lung, stomach and meso- and meta-nephric kidney. Comparison of the spatial domains of expression of mouse homeobox genes reveals a pattern consistent with the idea that they play a role in anteroposterior positional specification during embryogenesis.

Authors
Hogan, BL; Holland, PW; Lumsden, A
MLA Citation
Hogan, BL, Holland, PW, and Lumsden, A. "Expression of the homeobox gene, Hox 2.1, during mouse embryogenesis." Cell Differ Dev 25 Suppl (November 1988): 39-44. (Review)
PMID
2905204
Source
pubmed
Published In
Cell Differentiation and Development
Volume
25 Suppl
Publish Date
1988
Start Page
39
End Page
44

Characterization of the mouse SPARC/osteonectin gene. Intron/exon organization and an unusual promoter region.

Two overlapping cosmids have been isolated containing the entire murine gene for SPARC (osteonectin), a Ca2+-binding, phosphorylated glycoprotein associated with extracellular matrix synthesis and remodeling. The gene contains 10 exons and covers 26.5 kilobase pairs of DNA. Exon analysis shows that the two N-terminal glutamic acid-rich sequences which are predicted to undergo conformational change upon binding of calcium, as well as the C-terminal EF-hand Ca2+-binding domain are each encoded by a single exon. Comparative analysis of the exon sequence does not support the idea that the SPARC gene has evolved by shuffling of exons from other Ca2+-binding proteins. The 5' flanking region of the SPARC gene, which promotes transcription when placed in front of the bacterial chloramphenicol acetyltransferase gene, contains neither "TATA" nor "CAAT" box sequences. However, unlike most other genes lacking these motifs, mapping of the 5' end of the SPARC gene by RNase protection and primer extension analysis reveals only a single major and one minor transcription start site. The upstream region to -120 includes six repeats of the sequence GGAGG, two repeats of the sequence 5' GGAGG A/C GGAGGG 3', and a potential transcription factor AP-2 binding site.

Authors
McVey, JH; Nomura, S; Kelly, P; Mason, IJ; Hogan, BL
MLA Citation
McVey, JH, Nomura, S, Kelly, P, Mason, IJ, and Hogan, BL. "Characterization of the mouse SPARC/osteonectin gene. Intron/exon organization and an unusual promoter region." J Biol Chem 263.23 (August 15, 1988): 11111-11116.
PMID
3165375
Source
pubmed
Published In
The Journal of biological chemistry
Volume
263
Issue
23
Publish Date
1988
Start Page
11111
End Page
11116

Expression of homeo box genes during mouse development: a review.

Authors
Holland, PW; Hogan, BL
MLA Citation
Holland, PW, and Hogan, BL. "Expression of homeo box genes during mouse development: a review." Genes Dev 2.7 (July 1988): 773-782. (Review)
PMID
2905315
Source
pubmed
Published In
Genes & development
Volume
2
Issue
7
Publish Date
1988
Start Page
773
End Page
782

Developmental expression of 2ar (osteopontin) and SPARC (osteonectin) RNA as revealed by in situ hybridization.

2ar has been identified as a gene inducible by tumor promoters and growth factors in a variety of cultured mouse cell lines (Smith, J. H., and D. T. Denhardt. 1987. J. Cell. Biochem. 34:13-22). Sequence analysis shows that it codes for mouse osteopontin, an RGDS-containing, phosphorylated, sialic acid-rich Ca++-binding protein originally isolated from bone (Oldberg, A., A. Franzen, and D. Heinegard. 1986. Proc. Natl. Acad. Sci. USA. 83:8819-8823; Prince, C. W., T. Oosawa, W. T. Butler, M. Tomana, A. S. Brown, and R. E. Schrohenloer. 1987. J. Biol. Chem. 262:2900-3907.). In this paper we use Northern blot analysis and in situ hybridization to localize expression of 2ar during mouse embryogenesis. 2ar RNA is first detected in developing limb bones and calvaria at 14.5 d p.c., in a population of cells distinct from those expressing SPARC (osteonectin). High levels of 2ar expression are also seen in the bone marrow-derived granulated metrial gland cells of the deciduum and placenta, and in a number of epithelial tissues, including embryonic and postnatal kidney tubules, uterine epithelium and sensory epithelium of the embryonic ear. The temporal and spatial pattern of 2ar expression seen in vivo suggests that the protein plays a wider role than previously realized, in processes which are not confined to bone development.

Authors
Nomura, S; Wills, AJ; Edwards, DR; Heath, JK; Hogan, BL
MLA Citation
Nomura, S, Wills, AJ, Edwards, DR, Heath, JK, and Hogan, BL. "Developmental expression of 2ar (osteopontin) and SPARC (osteonectin) RNA as revealed by in situ hybridization." J Cell Biol 106.2 (February 1988): 441-450.
PMID
3339096
Source
pubmed
Published In
The Journal of Cell Biology
Volume
106
Issue
2
Publish Date
1988
Start Page
441
End Page
450

Spatially restricted patterns of expression of the homeobox-containing gene Hox 2.1. during mouse embryogenesis.

The mouse Hox 2.1 gene contains a homeobox sequence and is therefore a candidate for a vertebrate gene involved in the control of embryonic patterning or positional specification. To investigate this possibility, we have used in situ hybridization to determine the pattern of Hox 2.1 expression during mouse embryogenesis. At 8.5 days post coitum, Hox 2.1 is expressed at a low level in the posterior neuroectoderm and mesoderm, and in the neuroectoderm of the presumptive hindbrain. At 12.5 days p.c., Hox 2.1 is expressed in an anteroposterior restricted domain extending from the hindbrain throughout the length of the spinal cord, predominantly in the dorsal region. Between 12.5 and 13.5 days p.c. the domain becomes localized to the occipital and cervical regions. We also detect Hox 2.1 RNA in the embryonic lung, stomach, mesonephros and metanephros, as well as in myenteric plexus, dorsal root ganglia and the nodose ganglion, and in mature granulocytes. The embryonic expression of Hox 2.1 in neural tissue is compared with that of Hox 3.1, which also shows anteroposterior restricted domains of gene expression. These patterns of expression are not clearly consistent with Hox 2.1 or Hox 3.1 having roles in segmental patterning. However, the data are consistent with these genes having regulatory roles in anteroposterior positional specification in the neuroectoderm and mesoderm, and suggest that Hox 2.1 may also have functions during organogenesis.

Authors
Holland, PW; Hogan, BL
MLA Citation
Holland, PW, and Hogan, BL. "Spatially restricted patterns of expression of the homeobox-containing gene Hox 2.1. during mouse embryogenesis." Development 102.1 (January 1988): 159-174.
PMID
2458220
Source
pubmed
Published In
Development (Cambridge)
Volume
102
Issue
1
Publish Date
1988
Start Page
159
End Page
174

Molecular analysis of the cDNA for human SPARC/osteonectin/BM-40: sequence, expression, and localization of the gene to chromosome 5q31-q33.

Human cDNA clones encoding the extracellular calcium-binding, acidic glycoprotein known as SPARC, osteonectin, or BM-40 were isolated from a placental cDNA library. Two polyadenylated transcripts of 2.2 and 3.0 kb were detected in human tissues and cultured cells by Northern blot analysis, and cDNAs for both transcripts were characterized. The 2133-bp sequence of the more abundant (major) transcript contains an open reading frame for 303 amino acids. The deduced polypeptide has extensive amino acid sequence identity with mouse SPARC. The larger and minor 3.0-kb cDNA has an identical coding region but utilizes a downstream polyadenylation signal. Gene localization studies have revealed a single chromosomal site at 5q31-q33 by somatic cell hybrid analysis and in situ chromosomal hybridization. Furthermore, pulsed-field gel electrophoresis of human genomic DNA cleaved with different rare-cutting restriction enzymes and hybridized with SPARC cDNA probes revealed single or double fragments of less than 50 to about 150 kb. The evidence is consistent with a single locus for SPARC in humans. The gene was found to be differentially expressed in many human tissues and in an osteogenic sarcoma, but not in other transformed cells.

Authors
Swaroop, A; Hogan, BL; Francke, U
MLA Citation
Swaroop, A, Hogan, BL, and Francke, U. "Molecular analysis of the cDNA for human SPARC/osteonectin/BM-40: sequence, expression, and localization of the gene to chromosome 5q31-q33." Genomics 2.1 (January 1988): 37-47.
PMID
2838412
Source
pubmed
Published In
Genomics
Volume
2
Issue
1
Publish Date
1988
Start Page
37
End Page
47

Temporal and tissue-specific expression of distinct retrovirus-like (VL30) elements during mouse development.

We have analyzed the expression of VL30 retroviral RNA transcripts during mouse embryogenesis. VL30 RNA was found in all tissues examined from mid-gestation, but increased dramatically at later times in the extraembryonic amnion and visceral yolk sac, and to a lesser extent in embryonic liver. The overall temporal and tissue-specific pattern of expression was unlike that of other retrotransposon gene families. S1 nuclease mapping experiments which distinguish transcripts from distinct VL30 elements suggest that they are independently regulated in different tissues during mouse development.

Authors
Norton, JD; Hogan, BL
MLA Citation
Norton, JD, and Hogan, BL. "Temporal and tissue-specific expression of distinct retrovirus-like (VL30) elements during mouse development." Dev Biol 125.1 (January 1988): 226-228.
PMID
2824257
Source
pubmed
Published In
Developmental Biology
Volume
125
Issue
1
Publish Date
1988
Start Page
226
End Page
228

Expression of the homeobox genes Hox 2.1 and 2.6 during mouse development.

Authors
Graham, A; Holland, PW; Lumsden, A; Krumlauf, R; Hogan, BL
MLA Citation
Graham, A, Holland, PW, Lumsden, A, Krumlauf, R, and Hogan, BL. "Expression of the homeobox genes Hox 2.1 and 2.6 during mouse development." Curr Top Microbiol Immunol 137 (1988): 87-93.
PMID
2901327
Source
pubmed
Published In
Current topics in microbiology and immunology
Volume
137
Publish Date
1988
Start Page
87
End Page
93

Small eye (Sey): a mouse model for the genetic analysis of craniofacial abnormalities.

Small eye (Sey) is a dominant mutation in the mouse affecting the embryonic development of the eyes and nose. In homozygous Sey/Sey embryos, the optic vesicles grow out but there is no lens induction and the nasal pits fail to develop. Scanning electron microscope studies of Sey/Sey embryos show that the maxillary processes develop normally and fuse with ridges of ectoderm in the frontonasal position. In Sey/+ heterozygotes, the vacuolated lens is smaller than normal, and there is folding of the margins of the optic cup and ingrowth of mesodermal cells. Evidence is presented that Sey is not allelic with Coloboma (Cm), another mutation affecting eye development on chromosome 2.

Authors
Hogan, BL; Hirst, EM; Horsburgh, G; Hetherington, CM
MLA Citation
Hogan, BL, Hirst, EM, Horsburgh, G, and Hetherington, CM. "Small eye (Sey): a mouse model for the genetic analysis of craniofacial abnormalities." Development 103 Suppl (1988): 115-119.
PMID
3250848
Source
pubmed
Published In
Development (Cambridge)
Volume
103 Suppl
Publish Date
1988
Start Page
115
End Page
119

Getting nearer the mark

Authors
Hogan, B; Lyons, K
MLA Citation
Hogan, B, and Lyons, K. "Getting nearer the mark." Nature 336.6197 (1988): 304-305.
PMID
3194014
Source
scival
Published In
Nature
Volume
336
Issue
6197
Publish Date
1988
Start Page
304
End Page
305

A morphological analysis endocrine tumour genesis in pancreas and anterior pituitary of AVP/SV40 transgenic mice

Insertion into the mouse genome of the hybrid oncogene made up of bovine vasopressin gene derived 5′ upstream sequences and the coding sequences of SV40 large T-antigen promoted tumours in anterior pituitary and endocrine pancreas of mice bearing this transgene. In order to investigate the morphology of the steps in the neoplastic process, we used light and electron microscopy to study these organs in 42 animals belonging to the 3rd, 4th and 5th generations, subdivided into 4 age groups from 20 days to 100 days of life. Antibodies to large T-antigen were used to identify sites of expression of the hybrid oncogene, thus monitoring the steps in neoplastic transformation. Large T-antigen immunoreactivity was identified in dysplastic lesions of younger animals and in both dysplastic lesions and tumours of older mice. Insulin (100% of cases) and pancreatic polypeptide (25% of cases) immunoreactivities were revealed in pancreatic lesions but no hormonal immunoreactivity was detected in the pituitary lesions. The ultrastructural study confirmed that the majority cell population of the pancreatic neoplasms was B-type and that the anterior pituitary tumours were poorly granulated. The subcellular localization of large T-antigen immunoreactivity was investigated by the immunogold method and was confined to the heterochromatin of tumour cell nuclei. These findings provide evidence for the dysplasia-neoplasia sequence in the genesis of endocrine tumours of pituitary and pancreas of transgenic mice. The vasopressin-SV40 large T-antigen transgenic mice may therefore be an useful model for the study of endocrine cell oncogenesis, © 1988 Springer-Verlag.

Authors
Rindi, G; Bishop, AE; Murphy, D; Solcia, E; Hogan, B; Polak, JM
MLA Citation
Rindi, G, Bishop, AE, Murphy, D, Solcia, E, Hogan, B, and Polak, JM. "A morphological analysis endocrine tumour genesis in pancreas and anterior pituitary of AVP/SV40 transgenic mice." Virchows Archiv A Pathological Anatomy and Histopathology 412.3 (1988): 255-266.
PMID
2829418
Source
scival
Published In
Virchows Archiv - A Pathological Anatomy and Histopathology
Volume
412
Issue
3
Publish Date
1988
Start Page
255
End Page
266
DOI
10.1007/BF00737150

In vivo expression of mRNA for the Ca++-binding protein SPARC (osteonectin) revealed by in situ hybridization.

In situ hybridization is used to survey the tissue-specific and developmental expression of the cloned mouse gene Sparc, coding for a protein homologous to the bovine Ca++-binding protein, osteonectin. High levels of SPARC RNA are found in osteoblasts and odontoblasts. In addition, high grain counts are associated with a variety of other cell types in the embryo and newborn mouse, including parietal endoderm, deciduum, whisker follicles (connective tissue sheath), peripheral nerve trunk, skin (dermis), and stomach (submucosa). Spatially restricted but high levels of SPARC mRNA are also seen in the adult adrenal glands, testis, and ovary. This pattern of differential gene expression demands a reassessment of the function originally proposed for osteonectin, and predicts a much wider role for the protein in a variety of biological processes.

Authors
Holland, PW; Harper, SJ; McVey, JH; Hogan, BL
MLA Citation
Holland, PW, Harper, SJ, McVey, JH, and Hogan, BL. "In vivo expression of mRNA for the Ca++-binding protein SPARC (osteonectin) revealed by in situ hybridization." J Cell Biol 105.1 (July 1987): 473-482.
PMID
2440898
Source
pubmed
Published In
The Journal of Cell Biology
Volume
105
Issue
1
Publish Date
1987
Start Page
473
End Page
482

Transcription of H-2 and Qa genes in embryonic and adult mice.

We have isolated cDNAs for three class I genes from an 8.5-day C57Bl/6 mouse embryo cDNA library. Two of these cDNAs encode the classical transplantation antigens, H-2Kb and H-2Db. The third is a novelly spliced form of a Qa region gene, Q9, which lacks several exons including that encoding the transmembrane domain. Since this mRNA is detected on membrane-bound polysomes it may encode a secreted protein. Transcripts for these three genes and the pseudo-allele of Q9, Q7, were present at very low levels in the 8.5-day and 14.5-day embryo and in the 2-day neonate, compared to most adult tissues. Q10, the liver-specific secreted class I gene product in adults, is preferentially expressed in yolk sac and in fetal liver. We found no embryo-specific class I gene expression.

Authors
Fahrner, K; Hogan, BL; Flavell, RA
MLA Citation
Fahrner, K, Hogan, BL, and Flavell, RA. "Transcription of H-2 and Qa genes in embryonic and adult mice." EMBO J 6.5 (May 1987): 1265-1271.
PMID
3608979
Source
pubmed
Published In
EMBO Journal
Volume
6
Issue
5
Publish Date
1987
Start Page
1265
End Page
1271

Developmental and spatial patterns of expression of the mouse homeobox gene, Hox 2.1.

The Hox 2.1 gene forms part of a cluster of homeobox-containing genes on mouse chromosome 11. Analysis of Hox 2.1 cDNAs isolated from an 8 1/2-day p.c. mouse embryo library predicts that the gene encodes a 269 amino acid protein (Mr, 29,432). This deduced protein contains a homeobox 15 amino acids from the carboxy terminus and is very rich in serine and proline. A second partially conserved region present in several other genes containing homeoboxes, the hexapeptide Ile-Phe-Pro-Trp-Met-Arg, is located 12 amino acids upstream of the homeodomain and is encoded by a separate exon. Analysis of Hox 2.1 gene expression reveals a complex and tissue-specific series of RNA transcripts in a broad range of fetal tissues (lung, spinal cord, kidney, gut, spleen, liver and visceral yolk sac). Comparison of the temporal patterns of gene expression during development and in the adult suggests that Hox 2.1 is regulated independently in different tissues. Evidence is also presented that transcripts from other loci have extensive homology to the Hox 2.1 gene in sequences outside of the homeobox. In situ hybridization shows that Hox 2.1 transcripts are regionally localized in the spinal cord in an apparent anterior-posterior gradient extending from the hind brain. The distribution of RNA also displays a cell-type specificity in the lung, where mesodermal cells surrounding the branching epithelial cell layer accumulate high levels of Hox 2.1 transcripts.

Authors
Krumlauf, R; Holland, PW; McVey, JH; Hogan, BL
MLA Citation
Krumlauf, R, Holland, PW, McVey, JH, and Hogan, BL. "Developmental and spatial patterns of expression of the mouse homeobox gene, Hox 2.1." Development 99.4 (April 1987): 603-617.
PMID
2889591
Source
pubmed
Published In
Development (Cambridge)
Volume
99
Issue
4
Publish Date
1987
Start Page
603
End Page
617

Close genetic and physical linkage between the murine haemopoietic growth factor genes GM-CSF and Multi-CSF (IL3).

The two murine haemopoietic growth factors, granulocyte-macrophage colony stimulating factor (GM-CSF) and Multi-CSF (interleukin 3) stimulate the proliferation and differentiation of an overlapping set of haemopoietic progenitor cells and are produced coordinately following activation of T lymphocytes. Here we report the chromosomal location of the genes encoding these two factors. Initially both genes were assigned to chromosome 11 by analysis of mouse/Chinese hamster somatic cell hybrids. Genetic analysis using an interspecies (Mus musculus X Mus spretus) back-cross confirmed this assignment by demonstrating that both the GM-CSF and Multi-CSF genes are genetically linked to the SPARC gene, which had been independently assigned to sub-band B1 of chromosome 11. Analysis of physical distances by pulsed field gel electrophoresis demonstrated further that the two CSF genes lie within 230 kb of each other. However examination of the subchromosomal region containing all three loci by pulsed field gel analysis showed that SPARC is at least 400-500 kb distant from the region containing the two CSF genes.

Authors
Barlow, DP; Bućan, M; Lehrach, H; Hogan, BL; Gough, NM
MLA Citation
Barlow, DP, Bućan, M, Lehrach, H, Hogan, BL, and Gough, NM. "Close genetic and physical linkage between the murine haemopoietic growth factor genes GM-CSF and Multi-CSF (IL3)." EMBO J 6.3 (March 1987): 617-623.
PMID
3034600
Source
pubmed
Published In
EMBO Journal
Volume
6
Issue
3
Publish Date
1987
Start Page
617
End Page
623

Distinct patterns of glycosylation of colligin, a collagen-binding glycoprotein, and SPARC (osteonectin), a secreted Ca2+-binding glycoprotein. Evidence for the localisation of colligin in the endoplasmic reticulum.

Mouse parietal endoderm PYS cells were labelled with [2-3H]mannose for 16-24 h. Colligin, an Mr-47000 collagen-binding protein, and SPARC, a Mr-43000 protein, highly homologous to the Ca2+-binding protein osteonectin, were isolated from labelled cell extracts and culture medium respectively. Glycopeptides obtained by exhaustive digestion with pronase were analysed by lectin-affinity, ion-exchange, and gel-filtration chromatography and by paper chromatography of high-mannose oligosaccharides after endo H release. The results show that the N-linked carbohydrate chains of colligin are exclusively the high-mannose type, of which (Man)8(GlcNAc)2 and (Man)9(GlcNAc)2 make up 77%. This carbohydrate structure provides strong evidence that colligin is a component of the endoplasmic reticulum, and argues against a role in cell-surface interactions. By contrast to colligin, SPARC secreted by PYS cells contains predominantly a diantennary complex type of chain containing a variable number of sialic acid and core-substituted fucose residues. Similar glycosylation patterns to those discussed above were seen in colligin isolated from primary mouse embryonic parietal endoderm cells and the murine 3T3 cell line, and in SPARC secreted by bovine corneal endothelial cells. Unlike the type-IV-collagen-binding glycoprotein studied by Dennis, J., Waller, C. and Schirrmacher, V. [J. Cell Biol. 99, 1416-1423 (1984)], removal of N-linked oligosaccharides from colligin had no effect on its binding to native type IV collagen.

Authors
Hughes, RC; Taylor, A; Sage, H; Hogan, BL
MLA Citation
Hughes, RC, Taylor, A, Sage, H, and Hogan, BL. "Distinct patterns of glycosylation of colligin, a collagen-binding glycoprotein, and SPARC (osteonectin), a secreted Ca2+-binding glycoprotein. Evidence for the localisation of colligin in the endoplasmic reticulum." Eur J Biochem 163.1 (February 16, 1987): 57-65.
PMID
3816803
Source
pubmed
Published In
European journal of biochemistry / FEBS
Volume
163
Issue
1
Publish Date
1987
Start Page
57
End Page
65

Molecular cloning of laminin.

Authors
Barlow, DP; McVey, JH; Hogan, BL
MLA Citation
Barlow, DP, McVey, JH, and Hogan, BL. "Molecular cloning of laminin." Methods Enzymol 144 (1987): 464-474.
PMID
3626881
Source
pubmed
Published In
Methods in Enzymology
Volume
144
Publish Date
1987
Start Page
464
End Page
474

Calcium binding domains and calcium-induced conformational transition of SPARC/BM-40/osteonectin, an extracellular glycoprotein expressed in mineralized and nonmineralized tissues

SPARC, BM-40, and osteonectin are identical or very closely related extracellular proteins of apparent Mr 43 000 (Mr 33 000 predicted from sequence). They were originally isolated from parietal endoderm cells, basement membrane producing tumors, and bone, respectively, but are rather widely distributed in various tissues. In view of the calcium binding activity reported for osteonectin, we analyzed the SPARC sequence and found two putative calcium binding domains. One is an N-terminal acidic region with clusters of glutamic acid residues. This region, although neither γ-carboxylated nor homologous, resembles the γ-carboxyglutamic acid (Gla) domain of vitamin K dependent proteins of the blood clotting system in charge density, size of negatively charged clusters, and linkage to the rest of the molecule by a cysteine-rich domain. The other region is an EF-hand calcium binding domain located near the C-terminus. A disulfide bond between the E and F helix is predicted from modeling the EF-hand structure with the known coordinates of intestinal calcium binding protein. The disulfide bridge apparently serves to stabilize the isolated calcium loop in the extracellular protein. As observed for cytoplasmic EF-hand-containing proteins and for Gla domain containing proteins, a major conformational transition is induced in BM-40 upon binding of several Ca2+ ions. This is accompanied by a 35% increase in α-helicity. A pronounced sigmoidicity of the dependence of the circular dichroism signal at 220 nm on calcium concentration indicates that the process is cooperative. In view of its properties, abundance, and wide distribution, it is proposed that SPARC/ BM-40/osteonectin has a rather general regulatory function in calcium-dependent processes of the extracellular matrix. © 1987 American Chemical Society.

Authors
Engel, J; Taylor, W; Paulsson, M; Sage, H; Hogan, B
MLA Citation
Engel, J, Taylor, W, Paulsson, M, Sage, H, and Hogan, B. "Calcium binding domains and calcium-induced conformational transition of SPARC/BM-40/osteonectin, an extracellular glycoprotein expressed in mineralized and nonmineralized tissues." Biochemistry 26.22 (1987): 6958-6965.
PMID
3427055
Source
scival
Published In
Biochemistry
Volume
26
Issue
22
Publish Date
1987
Start Page
6958
End Page
6965

Engineering mutant mice

Authors
Hogan, B
MLA Citation
Hogan, B. "Engineering mutant mice." Nature 326.6110 (1987): 240-241.
PMID
3469525
Source
scival
Published In
Nature
Volume
326
Issue
6110
Publish Date
1987
Start Page
240
End Page
241

Mice transgenic for a vasopressin-SV40 hybrid oncogene develop tumors of the endocrine pancreas and the anterior pituitary. A possible model for human multiple endocrine neoplasia type 1

The authors have used transgenic mice to study the activity of a hybrid oncogene made up of 1.25 kb of 5' upstream sequences, derived from the bovine vasopressin gene, promoting the expression of the large T-antigen coding sequences of the early region of simian virus 40. Rather than promoting tumorigenesis in vasopressinergic cells of the hypothalamus, expression and activity of the hybrid oncogene, and consequent tumor formation, were confined to insulin-producing beta cells of the endocrine pancreas and to cells in the anterior pituitary. These observations suggest that the specificity of vasopressin gene expression normally results form an interaction between several regulatory elements, some of which are absent from the hybrid oncogene. The possible relationship between the endocrine tumor syndrome found in the vasopressin-SV40 transgenic mice and familial human multiple endocrine neoplasia is discussed.

Authors
Murphy, D; Bishop, A; Rindi, G; Murphy, MN; Stamp, GWH; Hanson, J; Polak, JM; Hogan, B
MLA Citation
Murphy, D, Bishop, A, Rindi, G, Murphy, MN, Stamp, GWH, Hanson, J, Polak, JM, and Hogan, B. "Mice transgenic for a vasopressin-SV40 hybrid oncogene develop tumors of the endocrine pancreas and the anterior pituitary. A possible model for human multiple endocrine neoplasia type 1." American Journal of Pathology 129.3 (1987): 552-566.
PMID
2827490
Source
scival
Published In
American Journal of Pathology
Volume
129
Issue
3
Publish Date
1987
Start Page
552
End Page
566

[26] Molecular cloning of laminin

Authors
Barlow, DP; McVey, JH; Hogan, BLM
MLA Citation
Barlow, DP, McVey, JH, and Hogan, BLM. "[26] Molecular cloning of laminin." Methods in Enzymology 144.C (1987): 464-474.
Source
scival
Published In
Methods in Enzymology
Volume
144
Issue
C
Publish Date
1987
Start Page
464
End Page
474
DOI
10.1016/0076-6879(87)44195-5

Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse.

Small eyes (Sey) is a semidominant, homozygous lethal mutation in the mouse (Roberts, 1967). It is allelic with SeyH, a radiation-induced homozygous prenatal lethal which has been mapped on chromosome 2. The effect of the Sey mutation is apparently limited to the growth and differentiation of the presumptive lens and nasal placodes. Homozygous Sey/Sey embryos can be distinguished as early as 10.5 days post coitum (p.c.); the optic vesicles grow out, but the ectoderm does not give rise to a lens and nasal pits never form. Immunohistochemical studies show that the distribution of the extracellular matrix glycoprotein laminin is not significantly different in the cephalic region of Sey/Sey versus Sey/+ or +/+ embryos. Sey/Sey embryos develop to term but without eyes or nose, and die soon after birth. Further analysis of Sey/Sey embryos may throw light on the mechanisms underlying morphogenesis of craniofacial structures in mammals.

Authors
Hogan, BL; Horsburgh, G; Cohen, J; Hetherington, CM; Fisher, G; Lyon, MF
MLA Citation
Hogan, BL, Horsburgh, G, Cohen, J, Hetherington, CM, Fisher, G, and Lyon, MF. "Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse." J Embryol Exp Morphol 97 (September 1986): 95-110.
PMID
3794606
Source
pubmed
Published In
Journal of Embryology and Experimental Morphology
Volume
97
Publish Date
1986
Start Page
95
End Page
110

Developmental and transformation-sensitive expression of the Sparc gene on mouse chromosome 11.

SPARC is a Mr 43,000 secreted, acidic, cysteine-rich glycoprotein homologous to 43K bovine endothelial 'culture shock' protein. We show here that it is encoded by a single gene localized to the central region of mouse chromosome 11. During development SPARC mRNA is expressed at higher levels in all the extra-embryonic tissues than in the fetus. Highest levels are found in the parietal endoderm, while visceral endoderm has approximately 6-fold less. This differential expression is also seen in F9 teratocarcinoma cells treated with retinoic acid under conditions in which they give rise to either parietal or visceral endoderm. The 20-fold increase seen during differentiation into parietal endoderm is due, at least in part, to an increase in gene transcription. We also report SPARC expression in a variety of adult tissues and cultured cells, and present evidence that a decrease accompanies the transformation of fibroblast cell lines.

Authors
Mason, IJ; Murphy, D; Münke, M; Francke, U; Elliott, RW; Hogan, BL
MLA Citation
Mason, IJ, Murphy, D, Münke, M, Francke, U, Elliott, RW, and Hogan, BL. "Developmental and transformation-sensitive expression of the Sparc gene on mouse chromosome 11." EMBO J 5.8 (August 1986): 1831-1837.
PMID
3758028
Source
pubmed
Published In
EMBO Journal
Volume
5
Issue
8
Publish Date
1986
Start Page
1831
End Page
1837

Evidence from molecular cloning that SPARC, a major product of mouse embryo parietal endoderm, is related to an endothelial cell 'culture shock' glycoprotein of Mr 43,000.

We describe the molecular cloning and characterization of a secreted, acidic, cysteine-rich glycoprotein (SPARC) of apparent Mr 43,000 which is a major product of mouse embryo parietal endoderm. These cells are specialized for the synthesis of a rapidly expanding basement membrane, but SPARC is not itself an integral matrix component. We show that SPARC is related structurally and antigenically to an Mr 43,000 glycoprotein secreted in large amounts by bovine aortic endothelial cells as part of a 'culture shock' response to in vitro conditions promoting their proliferation and migration.

Authors
Mason, IJ; Taylor, A; Williams, JG; Sage, H; Hogan, BL
MLA Citation
Mason, IJ, Taylor, A, Williams, JG, Sage, H, and Hogan, BL. "Evidence from molecular cloning that SPARC, a major product of mouse embryo parietal endoderm, is related to an endothelial cell 'culture shock' glycoprotein of Mr 43,000." EMBO J 5.7 (July 1986): 1465-1472.
PMID
3755680
Source
pubmed
Published In
EMBO Journal
Volume
5
Issue
7
Publish Date
1986
Start Page
1465
End Page
1472

The murine Hox-2 cluster of homeo box containing genes maps distal on chromosome 11 near the tail-short (Ts) locus.

Two probes derived from a mouse recombinant lambda-clone (H24.1), that contains a sequence closely homologous to the Drosophila antennapedia homeo box, were mapped to mouse chromosome (MMU) 11 by filter hybridization of somatic cell hybrid DNA. This sequence is highly homologous to a human homeo box gene (HOX2) and appears to represent one of the two genes in the Hox-2 cluster previously assigned to MMU 11. To regionally map the Hox-2 cluster, we have carried out in situ hybridization of the two H24.1 probes and of an independently isolated Hox-2 probe. The autoradiographic silver grain distributions were similar in all three experiments with a peak over band 11D. This region contains the locus for the tail-short (Ts) mutation which causes skeletal abnormalities in heterozygotes and early embryonic death in homozygotes.

Authors
Münke, M; Cox, DR; Jackson, IJ; Hogan, BL; Francke, U
MLA Citation
Münke, M, Cox, DR, Jackson, IJ, Hogan, BL, and Francke, U. "The murine Hox-2 cluster of homeo box containing genes maps distal on chromosome 11 near the tail-short (Ts) locus." Cytogenet Cell Genet 42.4 (1986): 236-240.
PMID
2875852
Source
pubmed
Published In
Cytogenetics and cell genetics
Volume
42
Issue
4
Publish Date
1986
Start Page
236
End Page
240

Phylogenetic distribution of Antennapedia-like homoeo boxes

The homoeo box is a conserved protein-coding DNA sequence present in several genes in arthropods, annelids and vertebrates. Two distinct classes of homoeo box have been identified - the Antennapedia (Antp) class and the engrailed class. In insects, both classes are found in genes involved in regulating development. We have therefore investigated the phylogenetic distribution of Antp-like homoeo boxes to explore the possiblity of a link between their presence and developmental strategy. The distribution data also give important insight into the origin of homoeo boxes and the phylogeny of the animal kingdom.

Authors
Holland, PW; Hogan, BLM
MLA Citation
Holland, PW, and Hogan, BLM. "Phylogenetic distribution of Antennapedia-like homoeo boxes." Nature 321.6067 (1986): 251-253.
Source
scival
Published In
Nature
Volume
321
Issue
6067
Publish Date
1986
Start Page
251
End Page
253

Linkage of genes for laminin B1 and B2 subunits on chromosome 1 in mouse.

We have used cDNA clones for the B1 and B2 subunits of laminin to find restriction fragment length DNA polymorphisms for the genes encoding these polypeptides in the mouse. Three alleles were found for LamB2 and two for LamB1 among the inbred mouse strains. The segregation of these polymorphisms among recombinant inbred strains showed that these genes are tightly linked in the central region of mouse Chromosome 1 between Sas-1 and Ly-m22, 7.4 +/- 3.2 cM distal to the Pep-3 locus. There is no evidence in the mouse for pseudogenes for these proteins.

Authors
Elliott, RW; Barlow, D; Hogan, BL
MLA Citation
Elliott, RW, Barlow, D, and Hogan, BL. "Linkage of genes for laminin B1 and B2 subunits on chromosome 1 in mouse." In Vitro Cell Dev Biol 21.8 (August 1985): 477-484.
PMID
2993224
Source
pubmed
Published In
In vitro cellular & developmental biology : journal of the Tissue Culture Association
Volume
21
Issue
8
Publish Date
1985
Start Page
477
End Page
484

Biosynthesis of EGF receptor, transferrin receptor and colligin by cultured human keratinocytes and the effect of retinoic acid.

The biosynthesis of EGF and transferrin receptor by human keratinocytes in culture has been followed using specific monoclonal antibodies. In addition, keratinocytes are shown to synthesise a Mr 47 000 protein that binds to gelatin-Sepharose. Peptide mapping confirms the identity of this protein with colligin, a newly described cell surface-associated glycoprotein that also binds to native collagens (Kurkinen et al., J biol chem 259 (1984) 5915) [9]. Vitamin A and its analogues have profound effects on the differentiation, morphology and motility of human keratinocytes in culture. We show here that retinoic acid (RA) has no effect on the growth rate of the cells or the synthesis of EGF receptor and colligin, but stimulates the synthesis of transferrin receptor.

Authors
Taylor, A; Hogan, BL; Watt, FM
MLA Citation
Taylor, A, Hogan, BL, and Watt, FM. "Biosynthesis of EGF receptor, transferrin receptor and colligin by cultured human keratinocytes and the effect of retinoic acid." Exp Cell Res 159.1 (July 1985): 47-54.
PMID
2993004
Source
pubmed
Published In
Experimental Cell Research
Volume
159
Issue
1
Publish Date
1985
Start Page
47
End Page
54

Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family.

The human type II collagen gene, COL2A1, has been assigned to chromosome 12, the type III gene, COL3A1, to chromosome 2, and one of the type IV genes, COL4A1, to chromosome 13. These assignments were made by using cloned genes as probes on Southern blots of DNA from a panel of mouse/human somatic cell hybrids. The two genes of type I collagen, COL1A1 and COL2A1, have been mapped previously to chromosomes 17 and 7, respectively. This family of conserved genes seems therefore to be dispersed throughout the genome.

Authors
Solomon, E; Hiorns, LR; Spurr, N; Kurkinen, M; Barlow, D; Hogan, BL; Dalgleish, R
MLA Citation
Solomon, E, Hiorns, LR, Spurr, N, Kurkinen, M, Barlow, D, Hogan, BL, and Dalgleish, R. "Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family." Proc Natl Acad Sci U S A 82.10 (May 1985): 3330-3334.
PMID
2987919
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
82
Issue
10
Publish Date
1985
Start Page
3330
End Page
3334

Tissue-specific gene expression in mouse F9 embryonal carcinoma cells: type IV collagen.

Authors
Kurkinen, M; Barlow, DP; Hogan, BL
MLA Citation
Kurkinen, M, Barlow, DP, and Hogan, BL. "Tissue-specific gene expression in mouse F9 embryonal carcinoma cells: type IV collagen." Ann N Y Acad Sci 460 (1985): 267-273.
PMID
3868951
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
460
Publish Date
1985
Start Page
267
End Page
273

Expression of c-fos in parietal endoderm, amnion and differentiating F9 teratocarcinoma cells.

The expression of the cellular proto-oncogene, c-fos, in extra-embryonic tissues of the mouse was investigated using a v-fos DNA probe and an affinity-purified antiserum raised against a C-terminal synthetic peptide. At 13.5 days of development, parietal endoderm--a tissue not previously studied using these methods--was found to express c-fos RNA at a higher level than the amnion or placenta. The previously reported dramatic increase in c-fos RNA levels in extra-embryonic membranes during gestation was found to be confined to the amnion. The antipeptide serum specifically recovered proteins with Mr values of 46,000 and 39,000 from extracts of parietal endoderm and amnion cells labelled for 15 min with 35S-methionine. On sodium-dodecyl-sulphate/polyacrylamide gel electrophoresis these proteins co-migrated with proteins immunoprecipitated using serum from rats inoculated with FBJ-MuSV-transformed cells (tumour-bearing rat serum). Pulse-chasing and 32P-labelling experiments showed that the protein with an Mr of 46,000 was rapidly converted into higher-molecular-weight phosphorylated derivatives. F9 teratocarcinoma stem cells differentiated into parietal-endoderm-like cells in response to treatment with retinoic acid and dibutyryl cyclic AMP. However, this differentiation was not accompanied by any large transient increase in c-fos RNA expression.

Authors
Mason, I; Murphy, D; Hogan, BL
MLA Citation
Mason, I, Murphy, D, and Hogan, BL. "Expression of c-fos in parietal endoderm, amnion and differentiating F9 teratocarcinoma cells." Differentiation 30.1 (1985): 76-81.
PMID
2419195
Source
pubmed
Published In
Differentiation
Volume
30
Issue
1
Publish Date
1985
Start Page
76
End Page
81

A mouse homoeo box gene is expressed during embryogenesis and in adult kidney

The homoeo box sequence of Drosophila is an element located in several genes that regulate segmentation and segment identity; it has homologues in the genomes of vertebrate species and a number of homoeo box-containing recombinant DNA clones have been isolated from Xenopus, man and mouse. In the present study we have isolated from a library of murine DNA a recombinant λ clone (H24.1) which contains a sequence closely homologous to the homoeo box within the Drosophila Antennapedia (Antp) gene. The protein sequence of the homoeo domain is identical to that encoded by Hu-1, one of a pair of closely linked homoeo boxes in the human genome. We have used a sensitive RNase protection assay to examine transcription of the H24.1 gene during mouse development, and in adult tissues. We report that the gene is transcribed from as early as 7.5 days post coitum (p.c.), with maximum expression at days 11.5 and 12.5 p.c. The transcript is enriched in embryonic spinal cord and brain at day 12.5 p.c., and in adult kidney.

Authors
Jackson, IJ; Schofield, P; Hogan, B
MLA Citation
Jackson, IJ, Schofield, P, and Hogan, B. "A mouse homoeo box gene is expressed during embryogenesis and in adult kidney." Nature 317.6039 (1985): 745-748.
PMID
4058581
Source
scival
Published In
Nature
Volume
317
Issue
6039
Publish Date
1985
Start Page
745
End Page
748

How is the mouse segmented?

During mouse embryogenesis the vertebrae, ribs, muscles and dermis are all derived from about 65 paired blocks of mesodermal cells - the somites - which are laid down sequentially along the body axis. This pattern of body segmentation is compared with that found in other organisms, in particular Drosophila. Mouse mutants have been described which have defects in somite patter but it seems that none show homeotic-like switches in segment identity. © 1985.

Authors
Hogan, B; Holland, P; Schofield, P
MLA Citation
Hogan, B, Holland, P, and Schofield, P. "How is the mouse segmented?." Trends in Genetics 1.C (1985): 67-74.
Source
scival
Published In
Trends in Genetics
Volume
1
Issue
C
Publish Date
1985
Start Page
67
End Page
74

Developmental biology: Homoeo boxes and strings for the packaging of genes?

Authors
Hogan, B
MLA Citation
Hogan, B. "Developmental biology: Homoeo boxes and strings for the packaging of genes?." Nature 314.6013 (1985): 670-671.
PMID
4039414
Source
scival
Published In
Nature
Volume
314
Issue
6013
Publish Date
1985
Start Page
670
End Page
671
DOI
10.1038/314670a0

Sequencing of laminin B chain cDNAs reveals C-terminal regions of coiled-coil alpha-helix.

cDNAs for laminin B chains have been isolated from a parietal endoderm cDNA library in pUC8 and pUC9. Identification is based on: ability to direct the synthesis in Escherichia coli of polypeptides carrying laminin antigen determinants, in vitro translation of hybrid selected mRNA, and hybridization to high mol. wt. RNA differentially expressed in cells synthesizing large amounts of laminin. The plasmid pPE9 hybrid selects mRNA for the B2 (mol. wt. 185 000) chain and provides 217 residues of C-terminal amino acid sequence. The plasmids pPE386 and 49 both hybrid select mRNAs for the B1a (mol. wt. 205 000) and B1b (mol. wt. 200 000) chains. These two cDNAs are identical over much of their sequence, but pPE386 includes 133 nucleotides of 3' non-coding sequence and a poly(A) tail. Together they provide 495 residues of C-terminal amino acid sequence. Analysis of the predicted sequences reveals a striking heptad repeat, with a high probability that residues a and d are hydrophobic. Such a repeat is typical of the coiled-coil alpha-helices found in proteins such as myosin, tropomyosin and desmin (2-stranded) and fibrinogen (3-stranded).

Authors
Barlow, DP; Green, NM; Kurkinen, M; Hogan, BL
MLA Citation
Barlow, DP, Green, NM, Kurkinen, M, and Hogan, BL. "Sequencing of laminin B chain cDNAs reveals C-terminal regions of coiled-coil alpha-helix." EMBO J 3.10 (October 1984): 2355-2362.
PMID
6209134
Source
pubmed
Published In
EMBO Journal
Volume
3
Issue
10
Publish Date
1984
Start Page
2355
End Page
2362

Pattern of serum protein gene expression in mouse visceral yolk sac and foetal liver.

We have shown by molecular hybridisation that the mRNAs for albumin, transferrin, apolipoprotein-A1, and alpha 1-antitrypsin are expressed at high levels in mouse visceral yolk sac. In contrast, the mRNAs for contrapsin (a plasma protease inhibitor) and the major urinary proteins (MUPs) are not detected in the visceral yolk sac at any stage of embryonic development. Contrapsin and MUP mRNAs both appear late in liver development. These differences in expression suggest that the visceral yolk sac is more similar to the foetal than adult mouse liver in its pattern of gene expression. However, the developmental time course of expression of these mRNAs is different between the foetal liver and the yolk sac. Evidence is also presented that the visceral yolk sac synthesises and secretes other apolipoproteins in addition to apolipoprotein-A1. These results suggest that the visceral yolk sac and foetal liver, two tissues with different embryological lineages, perform similar functions but are independently programmed for expression of the same set of serum protein genes.

Authors
Meehan, RR; Barlow, DP; Hill, RE; Hogan, BL; Hastie, ND
MLA Citation
Meehan, RR, Barlow, DP, Hill, RE, Hogan, BL, and Hastie, ND. "Pattern of serum protein gene expression in mouse visceral yolk sac and foetal liver." EMBO J 3.8 (August 1984): 1881-1885.
PMID
6479150
Source
pubmed
Published In
EMBO Journal
Volume
3
Issue
8
Publish Date
1984
Start Page
1881
End Page
1885

Cell surface-associated proteins which bind native type IV collagen or gelatin.

Gelatin coupled to Sepharose has been used to isolate [35S]methionine-labeled polypeptides of Mr = 47,000, 56,000, 62,000, and 65,000 from the 12,000 X g supernatant of detergent extracts of mouse embryo parietal endoderm cells. The polypeptides can also be recovered from various established cell lines which synthesize type IV procollagen, and in these cells the Mr = 47,000 polypeptide is the major gelatin-binding component. Several lines of evidence, including the results of continuous labeling and pulse-chase experiments, show that the polypeptides are not derived by proteolytic cleavage of larger precursors and are distinct from fragments of fibronectin. The Mr = 47,000, 62,000, and 65,000 polypeptides all contain N-linked oligosaccharide side chains, as judged by their labeling with [3H]mannose and their sensitivity to tunicamycin. The Mr = 62,000 and 65,000 polypeptides can be resolved by two-dimensional gel electrophoresis into species with different isoelectric points, and the Mr = 47,000 has a pI of 7.5-8.0. None of the gelatin-binding polypeptides appear to accumulate in the culture medium, and the Mr = 47,000, 62,000, and 65,000 species are labeled in a lactoperoxidase-catalyzed iodination of intact cells, suggesting that they are associated with the cell surface. Only the Mr = 47,000 glycoprotein binds to native type IV collagen. Possible functions for these surface components in vivo are discussed.

Authors
Kurkinen, M; Taylor, A; Garrels, JI; Hogan, BL
MLA Citation
Kurkinen, M, Taylor, A, Garrels, JI, and Hogan, BL. "Cell surface-associated proteins which bind native type IV collagen or gelatin." J Biol Chem 259.9 (May 10, 1984): 5915-5922.
PMID
6715378
Source
pubmed
Published In
The Journal of biological chemistry
Volume
259
Issue
9
Publish Date
1984
Start Page
5915
End Page
5922

Expression of EGF receptor and transferrin by F9 and PC13 teratocarcinoma cells.

We document the time of appearance and the levels of two markers of differentiation during the formation of embryoid bodies by two embryonal carcinoma (EC) cell lines. Neither of these markers has been described before for EC cells differentiating in aggregate culture, and they further extend the identification and characterization of new cell types. Both F9 and PC13 EC cell lines form embryoid bodies (so-called because they resemble early mouse embryos) with an outer epithelial layer of visceral endoderm cells, after suspension culture in the presence of retinoic acid. However, the two cell lines differ in the procedures needed to initiate the differentiation process. Once floating aggregate cultures have been formed, the time course of the appearance of epidermal growth factor (EGF) receptors and of the secretion of transferrin are similar in both cell lines, although the levels differ. EGF receptors and transferrin are quantified by 125I-EGF binding assays and enzyme-linked immunosorbent assays (ELISA) using specific antibodies, respectively. The expression of EGF receptors increases about two fold while that of transferrin increases up to 40 fold after treating F9 aggregates with retinoic acid. The EGF receptors reach a maximum 4 days after adding retinoic acid and then decline, while transferrin only increases later from a low but detectable level. For PC13 cells, EGF receptors increase tenfold, and transferrin synthetic rate increases 40 fold during the time-course. Interestingly, unstimulated F9 cells in monolayer cultures also express low levels of these markers, while the levels in PC13 EC cells are barely detectable above background.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Adamson, ED; Hogan, BL
MLA Citation
Adamson, ED, and Hogan, BL. "Expression of EGF receptor and transferrin by F9 and PC13 teratocarcinoma cells." Differentiation 27.2 (1984): 152-157.
PMID
6090250
Source
pubmed
Published In
Differentiation
Volume
27
Issue
2
Publish Date
1984
Start Page
152
End Page
157

A scanning electron microscope study of the extraembryonic endoderm of the 8th-day mouse embryo.

Late primitive streak embryos were dissected to reveal the junction between the visceral (VE) and parietal (PE) extraembryonic endoderm. Scanning electron microscopy showed that the two cell types differ markedly in their surface morphology and intercellular organization: the VE cells have numerous apical microvilli and form part of a continuous epithelial layer, while the smoother PE cells are scattered individually over the surface of Reichert's membrane. One interpretation of the morphology of the junction between the two tissues is that visceral endoderm cells in this region are detaching from the epithelial layer, migrating on to Reichert's membrane and differentiating into parietal endoderm. Preparatory to this, the visceral endoderm cells in the junctional zone may undergo extensive reorganization of their surface membranes.

Authors
Hogan, BL; Newman, R
MLA Citation
Hogan, BL, and Newman, R. "A scanning electron microscope study of the extraembryonic endoderm of the 8th-day mouse embryo." Differentiation 26.2 (1984): 138-143.
PMID
6734987
Source
pubmed
Published In
Differentiation
Volume
26
Issue
2
Publish Date
1984
Start Page
138
End Page
143

Reichert's membrane as a model for studying the biosynthesis and assembly of basement membrane components.

The major components of Reichert's membrane (laminin, type IV procollagen, entactin and heparan sulphate proteoglycan) are all synthesized by the parietal endoderm cells of the mouse embryo. Fibronectin is found mainly on the trophoblast side of Reichert's membrane and does not appear to be a major structural component. Parietal endoderm cells are thought to differentiate and migrate as individual cells from the margins of the epithelial visceral endoderm layer. They may interact with the type IV collagen in Reichert's membrane via a surface-associated protein of Mr = 47000 known as 'colligin'. Parietal endoderm cells are a rich source of mRNAs for basement membrane components and have been used to prepare a cDNA library in the expression vectors pUC8 and pUC9 from which cDNAs for type IV collagen and laminin B chains have been isolated.

Authors
Hogan, BL; Barlow, DP; Kurkinen, M
MLA Citation
Hogan, BL, Barlow, DP, and Kurkinen, M. "Reichert's membrane as a model for studying the biosynthesis and assembly of basement membrane components." Ciba Found Symp 108 (1984): 60-74.
PMID
6569831
Source
pubmed
Published In
Ciba Foundation symposium
Volume
108
Publish Date
1984
Start Page
60
End Page
74

Changes in the rate of laminin and entactin synthesis in F9 embryonal carcinoma cells treated with retinoic acid and cyclic amp.

The synthesis of laminin A and B chains, and of entactin, has been measured in murine F9 embryonal carcinoma cells differentiating in response to retinoic acid and cyclic AMP. Undifferentiated cells synthesis low levels of laminin, amounting to approximately 0.02% of the [35S]methionine incorporated into cytoplasmic protein during a 15-min pulse. After 6 days induction, laminin synthesis has increased 15- to 20-fold. Undifferentiated F9 cells synthesise more intracellular laminin B2 chains (Mr 225,000) than B1 chains (Mr 225,000), but the excess B2 chains are apparently not assembled into the secreted laminin molecule. Indirect immunofluorescence shows faint cytoplasmic staining and short fibrils of laminin between the undifferentiated F9 cells.

Authors
Cooper, AR; Taylor, A; Hogan, BL
MLA Citation
Cooper, AR, Taylor, A, and Hogan, BL. "Changes in the rate of laminin and entactin synthesis in F9 embryonal carcinoma cells treated with retinoic acid and cyclic amp." Dev Biol 99.2 (October 1983): 510-516.
PMID
6194034
Source
pubmed
Published In
Developmental Biology
Volume
99
Issue
2
Publish Date
1983
Start Page
510
End Page
516

Isolation of cDNA clones for basal lamina components: type IV procollagen.

We have isolated cDNA clones for mouse type IV procollagen from a library constructed from total poly A+RNA of 13.5 day mouse embryo parietal endoderm (PE) cells. In Northern analysis these clones hybridise to a 6.8 kb RNA which is abundant in embryonic PE cells and in differentiated F9 teratocarcinoma cells. Hybrid selection and in vitro translation of the cDNA specific mRNA produced a single polypeptide of Mr = 165 000. This polypeptide was specifically immunoprecipitated with mouse type IV procollagen antisera and comigrated on SDS-gel electrophoresis with one of the two in vitro synthesised chains of type IV procollagen. Undifferentiated F9 teratocarcinoma cells can be induced by retinoic acid and dibutyryl cAMP to differentiate in vitro into endoderm-like cells which resemble mouse PE cells in synthesising large amounts of basement membrane proteins, including type IV procollagen. Here we show, using one of the cDNA clones as a probe for type IV procollagen, that an increase in cellular concentration of type IV procollagen mRNA occurs within 24 to 48 hours of induction, reaching a constant high level by 72 hours.

Authors
Kurkinen, M; Barlow, DP; Helfman, DM; Williams, JG; Hogan, BL
MLA Citation
Kurkinen, M, Barlow, DP, Helfman, DM, Williams, JG, and Hogan, BL. "Isolation of cDNA clones for basal lamina components: type IV procollagen." Nucleic Acids Res 11.18 (September 24, 1983): 6199-6209.
PMID
6312413
Source
pubmed
Published In
Nucleic Acids Research
Volume
11
Issue
18
Publish Date
1983
Start Page
6199
End Page
6209

Co-expression of vimentin and cytokeratins in parietal endoderm cells of early mouse embryo.

Of the five classes of intermediate filaments found in vertebrate tissues, the cytokeratins are considered unique to epithelial tissues, while vimentin is expressed by endothelial and mesenchymal cells. In neither case is the precise function of the filament system known. Epithelial cells in culture often express vimentin as well as cytokeratins, but co-expression in vivo, as reported for pleomorphic adenomas of the parotid gland and metastatic carcinoma cells in ascites or pleural fluid, is still controversial. Here we report the co-expression of cytokeratins and vimentin in situ, in the parietal endoderm of the mouse embryo 8.5-13.5 days old. This population of individual, motile cells seems to be derived from a conventional epithelium by migration and differentiation. Our results support the idea that vimentin expression is specifically related to reduced cell-to-cell contact, and to the independent existence of a cell following detachment from an epithelial sheet.

Authors
Lane, EB; Hogan, BL; Kurkinen, M; Garrels, JI
MLA Citation
Lane, EB, Hogan, BL, Kurkinen, M, and Garrels, JI. "Co-expression of vimentin and cytokeratins in parietal endoderm cells of early mouse embryo." Nature 303.5919 (June 23, 1983): 701-704.
PMID
6190091
Source
pubmed
Published In
Nature
Volume
303
Issue
5919
Publish Date
1983
Start Page
701
End Page
704

In vitro synthesis of laminin and entactin polypeptides.

Total RNA and poly(A+) RNA, isolated from 13.5-day-old mouse embryo parietal endoderm cells and from differentiated F9 teratocarcinoma cells that synthesize laminin and entactin, were translated in the reticulocyte lysate. Antiserum raised against purified and denatured laminin B chains specifically immunoprecipitated from the translation reaction polypeptides of Mr = 205,000, 200,000, and 185,000. Antiserum against the native complex of laminin and entactin also immunoprecipitated these polypeptides, although less efficiently. In addition, this antiserum immunoprecipitated polypeptides of Mr = 300,000, 270,000, and 140,000. Antiserum against purified and denatured entactin immunoprecipitated only the Mr = 140,000 polypeptide. In contrast, no polypeptides were immunoprecipitated from translation reactions programmed with RNA from undifferentiated F9 cells that produce only small amounts of laminin and entactin. The in vitro synthesized polypeptides migrate on NaDodSO4-polyacrylamide gel electrophoresis slower than the respective unglycosylated laminin and entactin chains isolated from cells treated with tunicamycin. Supplementing the reticulocyte lysate with dog pancreas microsomal membranes yields in vitro translation products which co-migrate with the respective glycosylated laminin and entactin chains of control cells. Taken together, these results suggest that the polypeptides described represent in vitro synthesized laminin and entactin chains.

Authors
Kurkinen, M; Barlow, DP; Jenkins, JR; Hogan, BL
MLA Citation
Kurkinen, M, Barlow, DP, Jenkins, JR, and Hogan, BL. "In vitro synthesis of laminin and entactin polypeptides." J Biol Chem 258.10 (May 25, 1983): 6543-6548.
PMID
6189826
Source
pubmed
Published In
The Journal of biological chemistry
Volume
258
Issue
10
Publish Date
1983
Start Page
6543
End Page
6548

Molecular biology: Enhancers, chromosome position effects, and transgenic mice

Authors
Hogan, B
MLA Citation
Hogan, B. "Molecular biology: Enhancers, chromosome position effects, and transgenic mice." Nature 306.5941 (1983): 313-314.
PMID
6646213
Source
scival
Published In
Nature
Volume
306
Issue
5941
Publish Date
1983
Start Page
313
End Page
314
DOI
10.1038/306313a0

Carbohydrate changes in pre- and peri-implantation mouse embryos as detected by a monoclonal antibody

We have examined the tissue and embryonic distribution of an antigen on a large polysaccharide that is recognized by a monoclonal antibody, IIC3, prepared against F9 teratocarcinoma cells. By immunofluorescence the antigen is first detected on compacted morulae and early blastocysts. It is strongly expressed on the primary endoderm and trophoblast of expanded blastocysts, but then disappears from the trophoblast of attached blastocysts in vitro. The binding of the antibody is completely inhibited by d-galactose and N-acetylgalactosamine. Fluoresceinated lectins were used to study further the changes in cell surface carbohydrates on trophoblast during implantation. Ricinus I, specific for terminal galactose, binds to preimplantation stages but does not bind to the trophoblast of the attached blastocyst. On the other hand, wheat germ agglutinin, specific for N-acetylglucosamine and sialic acid, binds to all preimplantation embryos and also to attached blastocysts (embryo proper and trophoblast). Neuraminidase treatment of blastocyst outgrowths enhances binding of both IIC3 and Ricinus 1 to the trophoblast; conversely, the binding of wheat germ agglutinin is decreased by this treatment. The results obtained in this study show changes of cell surface carbohydrates during early mouse development and suggest that sialic acid may be masking molecules on the surface of the trophoblast at the time of implantation. © 1983.

Authors
Marticorena, P; Hogan, B; DiMeo, A; Artzt, K; Bennett, D
MLA Citation
Marticorena, P, Hogan, B, DiMeo, A, Artzt, K, and Bennett, D. "Carbohydrate changes in pre- and peri-implantation mouse embryos as detected by a monoclonal antibody." Cell Differentiation 12.1 (1983): 1-10.
PMID
6337728
Source
scival
Published In
Cell Differentiation
Volume
12
Issue
1
Publish Date
1983
Start Page
1
End Page
10

In vitro synthesis of type IV procollagen.

Total RNA was isolated from parietal endoderm cells of 131/2-day mouse embryos that synthesize large amounts of type IV procollagen. In vitro translation of this RNA in the reticulocyte lysate supplemented with a ribonuclease inhibitor yielded two equally prominent polypeptides of Mr = 165,000 and 168,000, immunoprecipitable with anti-mouse type IV collagen serum. The Mr = 165,000 polypeptide was shown by one-dimensional peptide mapping to represent an unmodified chain of type IV procollagen. The Mr = 168,000 polypeptide, the in vitro synthesis of which was barely detectable in the absence of a ribonuclease inhibitor, most likely represents the other genetically distinct chain of type IV procollagen. Similar results to those described were also obtained using poly(A) + RNA prepared from murine F9 embryonal carcinoma cells induced to differentiate in vitro into parietal endoderm.

Authors
Kurkinen, M; Foster, L; Barlow, DP; Hogan, BL
MLA Citation
Kurkinen, M, Foster, L, Barlow, DP, and Hogan, BL. "In vitro synthesis of type IV procollagen." J Biol Chem 257.24 (December 25, 1982): 15151-15155.
PMID
6184371
Source
pubmed
Published In
The Journal of biological chemistry
Volume
257
Issue
24
Publish Date
1982
Start Page
15151
End Page
15155

Chronic brucellosis--clinical response to reduction of suppressor T lymphocytes by cyclophosphamide/prednisone.

Authors
Thornes, RD; Early, AM; Hogan, BL; Reen, D
MLA Citation
Thornes, RD, Early, AM, Hogan, BL, and Reen, D. "Chronic brucellosis--clinical response to reduction of suppressor T lymphocytes by cyclophosphamide/prednisone." Ir Med J 75.11 (November 1982): 423-424.
PMID
7174262
Source
pubmed
Published In
Irish medical journal
Volume
75
Issue
11
Publish Date
1982
Start Page
423
End Page
424

Synthesis and localization of two sulphated glycoproteins associated with basement membranes and the extracellular matrix.

Two sulphated glycoproteins (sgps) of apparent molecular weight (Mr) 180,000 and 150,000, are synthesized by murine PYS and PF HR9 parietal endoderm and Swiss 3T3 cells. The Mr 150,000 sgp has a similar chemical structure to the sulphated glycoprotein, C, synthesized and laid down in Reichert's membrane by mouse embryo parietal endoderm cells (Hogan, B. L.M., A. Taylor, and A.R. Cooper, 1982, Dev. Biol., 90:210-214). Both the Mr 180,000 and 150,000 sgps are deposited in the detergent-insoluble matrix of cultured cells, but they do not apparently undergo any disulphide-dependent intermolecular interactions and are not precursors or products of each other. They contain asparagine-linked oligosaccharides, but these are not the exclusive sites of sulphate labeling. Antiserum raised against the Mr 150,000 sgp C of Reichert's membranes has been used in an immunohistochemical analysis of rat skin. In early foetal and adult skin the antigen is present only in basement membranes, but transiently before and after birth it is also found throughout the upper part of the dermis. This suggests that 150,000 sgp C is at times synthesized by nonepithelial cells and contributes to the extracellular matrix of mesenchymal tissues.

Authors
Hogan, BL; Taylor, A; Kurkinen, M; Couchman, JR
MLA Citation
Hogan, BL, Taylor, A, Kurkinen, M, and Couchman, JR. "Synthesis and localization of two sulphated glycoproteins associated with basement membranes and the extracellular matrix." J Cell Biol 95.1 (October 1982): 197-204.
PMID
7142285
Source
pubmed
Published In
The Journal of Cell Biology
Volume
95
Issue
1
Publish Date
1982
Start Page
197
End Page
204

Murine parietal endoderm cells synthesise heparan sulphate and 170K and 145K sulphated glycoproteins as components of Reichert's membrane.

Authors
Hogan, BL; Taylor, A; Cooper, AR
MLA Citation
Hogan, BL, Taylor, A, and Cooper, AR. "Murine parietal endoderm cells synthesise heparan sulphate and 170K and 145K sulphated glycoproteins as components of Reichert's membrane." Dev Biol 90.1 (March 1982): 210-214.
PMID
6460654
Source
pubmed
Published In
Developmental Biology
Volume
90
Issue
1
Publish Date
1982
Start Page
210
End Page
214

Localization of fibronectin, laminin-entactin, and entactin in Reichert's membrane by immunoelectron microscopy.

Immunoelectron microscopy using protein A-colloidal gold complexes of different sizes was used to study the relative distribution of extracellular matrix glycoproteins within Reichert's membrane (RM) of 13.5-day mouse embryos. Labelling for fibronectin was distributed asymmetrically; the highest concentration occurring in the outermost layer adjacent to the trophoblast cells and negligible labelling in the inner matrix, beneath the parietal endoderm cells. Within the main body of the membrane, fibronectin was concentrated in discrete electron-opaque deposits. Antibodies raised against the native complex between laminin and entactin , and against entactin alone labelled the RM more uniformly.

Authors
Semoff, S; Hogan, BL; Hopkins, CR
MLA Citation
Semoff, S, Hogan, BL, and Hopkins, CR. "Localization of fibronectin, laminin-entactin, and entactin in Reichert's membrane by immunoelectron microscopy." EMBO J 1.10 (1982): 1171-1175.
PMID
7188248
Source
pubmed
Published In
EMBO Journal
Volume
1
Issue
10
Publish Date
1982
Start Page
1171
End Page
1175

Studies on the biosynthesis of laminin by murine parietal endoderm cells.

The biosynthesis and processing of the polypeptides A (Mr = 450 x 10(3)), B1 (Mr = 240 x 10(3)), B2 (Mr = 230 x 10(3)) and C (Mr = 150 x 10(3)) of the extracellular matrix protein, laminin, were studied in murine parietal endoderm cells labelled with [35S]methionine. Various lines of evidence suggest that the A chains are not precursors to the smaller B chains. Firstly, the pulse-chase experiments, radioactivity in cytoplasmic A and (B1 + B2) chains declines with the same half-life of about 70 min. Secondly, peptide maps generated by digestion of A and B (B1 + B2) chains with Staphylococcus aureus V8 protease are different. Finally, rabbit antibodies to isolated, denatured (B1 + B2) chains do not cross-react with reduced and alkylated A chains. A, B1, B2 and C polypeptides are all glycosylated by an intracellular process involving the addition of tunicamycin and endo-beta-N-acetylglucosaminidase-H-sensitive N-linked oligosaccharide side chains. Further glycosylation probably occurs around the time of secretion. Disulphide bonding of some A and B chains can be observed in the cytoplasm within 10 min of adding [35S]methionine. However, it appears that some free A and B2 chains are present in the cytoplasm and that free A chains exist in the medium. The relationship between the 150 x 10(3)-Mr C glycoprotein and the A and B components is discussed. Although B and C chains generate different peptide maps after digestion with S. aureus V8 protease, antibodies raised against isolated, denatured C chains cross-react with reduced and alkylated B (but not A) chains. This suggests that B and C chains may share some antigenic determinant(s).

Authors
Cooper, AR; Kurkinen, M; Taylor, A; Hogan, BL
MLA Citation
Cooper, AR, Kurkinen, M, Taylor, A, and Hogan, BL. "Studies on the biosynthesis of laminin by murine parietal endoderm cells." Eur J Biochem 119.1 (September 1981): 189-197.
PMID
7341241
Source
pubmed
Published In
European journal of biochemistry / FEBS
Volume
119
Issue
1
Publish Date
1981
Start Page
189
End Page
197

Cell interactions modulate embryonal carcinoma cell differentiation into parietal or visceral endoderm.

Authors
Hogan, BL; Taylor, A; Adamson, E
MLA Citation
Hogan, BL, Taylor, A, and Adamson, E. "Cell interactions modulate embryonal carcinoma cell differentiation into parietal or visceral endoderm." Nature 291.5812 (May 21, 1981): 235-237.
PMID
6164928
Source
pubmed
Published In
Nature
Volume
291
Issue
5812
Publish Date
1981
Start Page
235
End Page
237

Cell interactions and endoderm differentiation in cultured mouse embryos.

Morphological and biochemical evidence is presented that the visceral extraembryonic endoderm of the 6.5-day mouse embryo will differentiate into parietal endoderm when cultured in contact with extraembryonic ectoderm undergoing transition into trophoblast giant cells. Egg cylinders from 6.5-day embryos were dissected into embryonic and extraembryonic halves and cultured in suspension in vitro for up to 7 days. After 4 days, the endoderm cells of the extraembryonic fragments morphologically resemble parietal endoderm, are associated with a thick basement membrane and synthesize large amounts of the matrix proteins laminin and Type IV procollagen. A similar transition in phenotype is not seen in the endoderm of embryonic fragments, nor in visceral extraembryonic endoderm cells cultured in isolation. In another series of experiments, complete egg cylinders were dissected free of visceral endoderm overlying the extraembryonic ectoderm and then cultured in vitro. The visceral endoderm cells which recolonize the surface of the extraembryonic ectoderm develop a parietal endoderm phenotype and lay down a thick basement membrane. These results suggest that the differentiation of the extraembryonic endoderm of the early mouse embryo into visceral and parietal phenotypes can be influenced by local cell-cell or cell-substrate interactions, and is not determined solely by cell lineage.

Authors
Hogan, BL; Tilly, R
MLA Citation
Hogan, BL, and Tilly, R. "Cell interactions and endoderm differentiation in cultured mouse embryos." J Embryol Exp Morphol 62 (April 1981): 379-394.
PMID
7276820
Source
pubmed
Published In
Journal of Embryology and Experimental Morphology
Volume
62
Publish Date
1981
Start Page
379
End Page
394

From embryo to teratocarcinoma in tissue culture

Authors
Hogan, B
MLA Citation
Hogan, B. "From embryo to teratocarcinoma in tissue culture." Nature 292.5819 (1981): 111-112.
PMID
7242680
Source
scival
Published In
Nature
Volume
292
Issue
5819
Publish Date
1981
Start Page
111
End Page
112
DOI
10.1038/292111b0

Integration of foreign genes into the mammalian germ line: Genetic engineering enters anew era

Authors
Hogan, B; Williams, J
MLA Citation
Hogan, B, and Williams, J. "Integration of foreign genes into the mammalian germ line: Genetic engineering enters anew era." Nature 294.5836 (1981): 9-10.
PMID
6945480
Source
scival
Published In
Nature
Volume
294
Issue
5836
Publish Date
1981
Start Page
9
End Page
10
DOI
10.1038/294009a0

Laminin and epithelial cell attachment

Authors
Hogan, B
MLA Citation
Hogan, B. "Laminin and epithelial cell attachment." Nature 290.5809 (1981): 737-738.
PMID
7219561
Source
scival
Published In
Nature
Volume
290
Issue
5809
Publish Date
1981
Start Page
737
End Page
738

Incorporation into Reichert's membrane of laminin-like extracellular proteins synthesized by parietal endoderm cells of the mouse embryo.

Authors
Hogan, BL; Cooper, AR; Kurkinen, M
MLA Citation
Hogan, BL, Cooper, AR, and Kurkinen, M. "Incorporation into Reichert's membrane of laminin-like extracellular proteins synthesized by parietal endoderm cells of the mouse embryo." Dev Biol 80.2 (December 1980): 289-300.
PMID
7450285
Source
pubmed
Published In
Developmental Biology
Volume
80
Issue
2
Publish Date
1980
Start Page
289
End Page
300

High molecular weight extracellular proteins synthesized by endoderm cells derived from mouse teratocarcinoma cells and normal extraembryonic membranes.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "High molecular weight extracellular proteins synthesized by endoderm cells derived from mouse teratocarcinoma cells and normal extraembryonic membranes." Dev Biol 76.2 (May 1980): 275-285.
PMID
7390005
Source
pubmed
Published In
Developmental Biology
Volume
76
Issue
2
Publish Date
1980
Start Page
275
End Page
285

In vitro development of inner cell masses isolated from t0/t0 and t(w5)/t(w5) mouse embryos

Inner cell masses (ICMs) isolated immunosurgically from mouse blastocysts segregating the homozygous lethal mutants t0/t0 and t(w5)/t(w5) were cultured in vitro. Presumed t0/t0 ICMs fail to grow after three days in culture (equivalent gestational day 7.5) when they consist of an outer layer of endoderm cells surrounding about 30 epiblast cells. Presumed homozygous t(w5)/t(w5) ICMs develop to a more advanced stage in culture and on the seventh day (equivalent gestational day 11.5) consist of an inner core of disorganized ectoderm cells with a small proamniotic cavity, surrounded by multiple layers of endoderm cells.

Authors
Hogan, B; Spiegelman, M; Bennet, D
MLA Citation
Hogan, B, Spiegelman, M, and Bennet, D. "In vitro development of inner cell masses isolated from t0/t0 and t(w5)/t(w5) mouse embryos." Journal of Embryology and Experimental Morphology VOL.60 (1980): 419-428.
PMID
7031163
Source
scival
Published In
Journal of Embryology and Experimental Morphology
Volume
VOL.60
Publish Date
1980
Start Page
419
End Page
428

Synthesis and retention of fibronectin (LETS protein) by mouse teratocarcinoma cells

Mouse teratocarcinoma cells in culture were examined for both the synthesis (by metabolic labelling) and surface accumulation (by indirect immunofluorescence) of fibronectin, a glycoprotein with subunits of molecular weight 220000 D known to form part of the extracellular matrix of many cells in vivo. Although lines of both pluripotent and nullipotent embryonal carcinoma cells synthesize the protein and release it into the medium, they do not retain it on their surfaces. Monolayers of the endoderm line PSA5-E both synthesize fibronectin and lay it down in an extracellular network. A line of PYS parietal endoderm cells does not retain surface fibronectin, although it does accumulate other extracellular matrix material. When pluripotent embryonal carcinoma cells differentiate into cystic embryoid bodies, fibronectin accumulates in a basement membrane below the outer endoderm cells (both visceral and parietal-like) and may play a transient role in organizing the inside cells into an epithelial layer. © 1978.

Authors
Wolfe, J; Mautner, V; Hogan, B; Tilly, R
MLA Citation
Wolfe, J, Mautner, V, Hogan, B, and Tilly, R. "Synthesis and retention of fibronectin (LETS protein) by mouse teratocarcinoma cells." Experimental Cell Research 118.1 (1979): 63-71.
PMID
365554
Source
scival
Published In
Experimental Cell Research
Volume
118
Issue
1
Publish Date
1979
Start Page
63
End Page
71

Epithelial cancer, differentiation, and vitamin A

Authors
Hogan, B
MLA Citation
Hogan, B. "Epithelial cancer, differentiation, and vitamin A." Nature 277.5694 (1979): 261-262.
PMID
763316
Source
scival
Published In
Nature
Volume
277
Issue
5694
Publish Date
1979
Start Page
261
End Page
262

Development in mammals

Authors
Hogan, B
MLA Citation
Hogan, B. "Development in mammals." Nature 276.5683 (1978): 100--.
Source
scival
Published In
Nature
Volume
276
Issue
5683
Publish Date
1978
Start Page
100-
DOI
10.1038/276100a0

In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. II. Inner cell masses from 3.5- to 4.0-day p.c. blastocysts

The paper describes the development in culture of inner cell masses isolated immunosurgically from C3H/He mouse blastocysts immediately after collection between 3.5 and 4.0 days p.c. By 24-48 h most of the inner cell masses isolated from half-expanded blastocysts, and about 50% of those from expanded blastocysts, regenerate an outer layer of trophectoderm-like cells and so resemble mini-blastocysts. With further in vitro culture these structures attach to the substratum and give rise to trophoblast-like giant cells, together with clusters of parietal endoderm cells or inner cell masses surrounded by visceral endoderm. Many of the inner cell masses from the remaining expanded blastocysts develop into floating structures with an outer layer of endoderm cells, and by 7 days consist of a large fluid filled cyst surrounding a collapsed vesicle of epithelial cells. Mesodermal cells line the cysts and form numerous blood islands. When mechanically disrupted, and grown as attached sheets of cells, these cystic structures give rise to patches of trophoblast-like giant cells similar to those described in the previous paper.

Authors
Hogan, B; Tilly, R
MLA Citation
Hogan, B, and Tilly, R. "In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. II. Inner cell masses from 3.5- to 4.0-day p.c. blastocysts." Journal of Embryology and Experimental Morphology VOL. 45 (1978): 107-121.
PMID
353213
Source
scival
Published In
Journal of Embryology and Experimental Morphology
Volume
VOL. 45
Publish Date
1978
Start Page
107
End Page
121

In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. I. Inner cell masses from 3.5-day p.c. blastocysts incubated for 24 h before immunosurgery

This paper describes the in vitro development of inner cell masses isolated immunosurgically from mouse blastocysts which had been collected on 3.5 days post coitum (p.c.), and then incubated for 24 hr. The inner cell masses continue to grow in culture and develop through a series of stages with increasing complexity of internal organization. By day 1 all of the cultured ICMs have an outer layer of endoderm, and by day 3 some of them have 2 distinct kinds of inside cells; a columnar epithelial layer and a thin hemisphere of elongated cells. Later, mesodermal cells appear to delaminate from a limited region of the columnar layer, close to where it forms a junction with the inner cells. By day 5, about 25% of the cultured ICMs have a striking resemblance to normal 7.5-day p.c. C3H embryos, with embryonic ectoderm, extra-embryonic ectoderm and chorion, embryonic and extra-embryonic mesoderm, and visceral endoderm. When mechanically disrupted and grown as attached clumps of cells in a tissue dish, these embryo-like structures give rise to trophoblast-like giant cells. These results suggest that the inner cell mass of 4.5-day p.c. blastocysts contains cells which can give rise to trophoblast derivates in culture.

Authors
Hogan, B; Tilly, R
MLA Citation
Hogan, B, and Tilly, R. "In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. I. Inner cell masses from 3.5-day p.c. blastocysts incubated for 24 h before immunosurgery." Journal of Embryology and Experimental Morphology VOL. 45 (1978): 93-105.
PMID
353217
Source
scival
Published In
Journal of Embryology and Experimental Morphology
Volume
VOL. 45
Publish Date
1978
Start Page
93
End Page
105

Isolation of a human teratoma cell line which expresses F9 antigen

THE F9 antigen, defined by antisera raised in syngeneic mice against pluripotent embryonal carcinoma cells, is present on early mouse embryos, spermatozoa and male germinal cells, but not on adult somatic tissues 1,2. This antigen, thought to be coded by gene(s) located at, or linked to, the developmentally important T/t complex, may play a part in early embryogenesis3-5. This idea is supported by the fact that the antigen seems to have been conserved during mammalian evolution. Anti-F9 activity is absorbed by sperm of several species including man, rat, rabbit and bull 5-7 and there is evidence for its presence on the morulae of rabbit, rat and cow, and on human foetal testicular cells2,5. The cross reaction of anti-F9 with human sperm suggested that undifferentiated stem cells in human teratocarcinomas might also carry F9 on their surface, and we report here the isolation of human teratocarcinoma cell line which expresses F9 antigen. © 1977 Nature Publishing Group.

Authors
Hogan, B; Fellous, M; Jacob, F; Avner, P
MLA Citation
Hogan, B, Fellous, M, Jacob, F, and Avner, P. "Isolation of a human teratoma cell line which expresses F9 antigen." Nature 270.5637 (1977): 515-518.
PMID
593370
Source
scival
Published In
Nature
Volume
270
Issue
5637
Publish Date
1977
Start Page
515
End Page
518
DOI
10.1038/270515a0

In vitro culture and differentiation of normal mouse blastocysts

When preimplantation mouse embryos are transplanted to extrauterine sites, up to 20% develop almost normally to the egg cylinder stage (equivalent to about 6-7 in utero). They then become disorganised and give rise to tumours, which are usually mature teratomas containing a wide range of differentiated tissues, but less frequently are progressively growing teratocarcinomas containing nests of undifferentiated pluripotent embryonal cells. There are many resons why it would be interesting to reproduce such normal and abnormal development efficiently in vitro. Although a number of techniques have been used to culture preimplantation embryos, none of them has proved entirely satisfactory; in the best conditions only 5-20% of 3.5-4 d blastocysts develop in vitro to form differentiated, foetal tissues. Most only give rise to extraembryonic endoderm and its associated mesoderm; these cell types proliferate extensively in vitro, and consequently most of the continuous lines derived from blastocyst cultures have probably originated from extraembryonic tissues. In this paper the authors describe a simple and reproducible method for culturing mouse blastocysts in vitro so that around 70% give rise to colonies which continue to grow for up to 4 weeks and produce a variety of differentiated tissues, including skin, nerve, beating muscle, cartilage and fibroblasts. The method relies on the technique of immunosurgery for killing and removing first the trophectoderm and then the hypoblast (primary endoderm) layers of the embryo, to yield clumps of isolated epiblast (embryonic ectoderm).

Authors
Hogan, B; Tilly, R
MLA Citation
Hogan, B, and Tilly, R. "In vitro culture and differentiation of normal mouse blastocysts." Nature 265.5595 (1977): 626-629.
PMID
323719
Source
scival
Published In
Nature
Volume
265
Issue
5595
Publish Date
1977
Start Page
626
End Page
629

Changes in the behaviour of teratocarcinoma cells cultivated in vitro.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Changes in the behaviour of teratocarcinoma cells cultivated in vitro." Nature 263.5573 (September 9, 1976): 136-137.
PMID
987543
Source
pubmed
Published In
Nature
Volume
263
Issue
5573
Publish Date
1976
Start Page
136
End Page
137

Teratocarcinoma cells can develop normally

Authors
Hogan, B
MLA Citation
Hogan, B. "Teratocarcinoma cells can develop normally." Nature 258.5530 (1975): 12-13.
Source
scival
Published In
Nature
Volume
258
Issue
5530
Publish Date
1975
Start Page
12
End Page
13
DOI
10.1038/258012a0

Effect of inhibitors of proteolytic enzymes on the growth of normal and polyoma transformed BHK cells.

Authors
McIlhinney, A; Hogan, BL
MLA Citation
McIlhinney, A, and Hogan, BL. "Effect of inhibitors of proteolytic enzymes on the growth of normal and polyoma transformed BHK cells." Biochem Biophys Res Commun 60.1 (September 9, 1974): 348-354.
PMID
4370770
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
60
Issue
1
Publish Date
1974
Start Page
348
End Page
354

Effect of growth conditions on the activity of ornithine decarboxylase in cultured hepatoma cells. II. Effect of serum and insulin.

Authors
Hogan, BL; McIlhinney, A; Murden, S
MLA Citation
Hogan, BL, McIlhinney, A, and Murden, S. "Effect of growth conditions on the activity of ornithine decarboxylase in cultured hepatoma cells. II. Effect of serum and insulin." J Cell Physiol 83.3 (June 1974): 353-357.
PMID
4151245
Source
pubmed
Published In
Journal of Cellular Physiology
Volume
83
Issue
3
Publish Date
1974
Start Page
353
End Page
357
DOI
10.1002/jcp.1040830305

Effect of growth conditions on the activity of ornithine decarboxylase in cultured hepatoma cells. I. Effect of amino acid supply.

Authors
Hogan, BL; Murden, S
MLA Citation
Hogan, BL, and Murden, S. "Effect of growth conditions on the activity of ornithine decarboxylase in cultured hepatoma cells. I. Effect of amino acid supply." J Cell Physiol 83.3 (June 1974): 345-351.
PMID
4363880
Source
pubmed
Published In
Journal of Cellular Physiology
Volume
83
Issue
3
Publish Date
1974
Start Page
345
End Page
351
DOI
10.1002/jcp.1040830304

Rapid degradation of puromycyl peptides in hepatoma cells and reticulocytes.

Authors
McIlhinney, A; Hogan, BL
MLA Citation
McIlhinney, A, and Hogan, BL. "Rapid degradation of puromycyl peptides in hepatoma cells and reticulocytes." FEBS Lett 40.2 (April 1, 1974): 297-301.
PMID
4369108
Source
pubmed
Published In
FEBS Letters
Volume
40
Issue
2
Publish Date
1974
Start Page
297
End Page
301

Effect of protease inhibitors on protein degradation in rat hepatoma cells I. Effect on general protein degradation

Tosyllysine chloromethyl ketone and tosylphenylalanine chloromethyl ketone in vitro are active-site specific and irreversible inhibitors of trypsin (EC 3.4.21.4) and chymotrypsin (EC. 3.4.21.1) respectively. Using rat hepatoma cells in suspension culture, both inhibitors were found to partially inhibit breakdown of prelabelled cell proteins ot amino acids, the effect being greastest in the absence of serum. Protein synthesis in rat hepatoma cells, reticulocytes and reticulyte lysates was also irreversibly inhibited by these compounds. Reduction of ATP levels with antimycin a inhibited protein degradation, but neither tosylphenylalanine chloromethyl ketone nor tosyllysine chloromethyl ketone had any effect on ATP concentration in rat hepatoma cells. These results suggest that the degradation of at least some proteins in animal cells may involve the action of serine protease(s). © 1974.

Authors
McIlhinney, A; Hogan, BLM
MLA Citation
McIlhinney, A, and Hogan, BLM. "Effect of protease inhibitors on protein degradation in rat hepatoma cells I. Effect on general protein degradation." BBA - General Subjects 372.2 (1974): 358-365.
Source
scival
Published In
BBA - General Subjects
Volume
372
Issue
2
Publish Date
1974
Start Page
358
End Page
365

Control of 3T3 cell growth

Authors
Hogan, B
MLA Citation
Hogan, B. "Control of 3T3 cell growth." Nature 249.5454 (1974): 214--.
Source
scival
Published In
Nature
Volume
249
Issue
5454
Publish Date
1974
Start Page
214-
DOI
10.1038/249214a0

Effect of cyclic nucleotides on the induction of ornithine decarboxylase in BHK cells by serum and insulin

Quiescent baby hamster kidney cells in 0.5% serum synthesize little DNA and have low levels of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. After adding serum to 5%, ODC activity is increased 30 fold, reaching a maximum at 6 hr, whereas DNA synthesis is reinitiated at 12 hr. Five μg/ml insulin also increases ODC activity 3 fold by 4 hr. In quiescent 3T3 cells and mouse embryo fibroblasts, serum and insulin may trigger many metabolic events by causing a transient drop in intracellular cyclic AMP and a rise in cyclic GMP. To test this hypothesis in BHK cells, cAMP levels were raised by adding dibutyryl cAMP and/or theophylline, or by stimulating adenylate cyclase with Prostaglandin E1. cAMP blocks the serum stimulation of DNA synthesis, but increases ODC activity, both in quiescent cells and in cells treated with serum and insulin. These results suggest that serum and insulin control ODC activity through a mechanism independent of a drop in cAMP. © 1974.

Authors
Hogan, B; Shields, R; Curtis, D
MLA Citation
Hogan, B, Shields, R, and Curtis, D. "Effect of cyclic nucleotides on the induction of ornithine decarboxylase in BHK cells by serum and insulin." Cell 2.4 (1974): 229-233.
PMID
4369950
Source
scival
Published In
Cell
Volume
2
Issue
4
Publish Date
1974
Start Page
229
End Page
233

Effect of protease inhibitors on protein degradation in rat hepatoma cells II. Effects on ornithine decarboxylase and tyrosine aminotransferase

Tyrosine aminotransferase (EC 2.6.1.5) and ornithine decarboxylase (EC 4.1.1.17) are both inducible, pyridoxal phosphate-requiring enzymes, which undergo rapid turnover in cultured rat hepatoma (HTC) cells, as measured by loss of enzyme activity following inhibition of protein synthesis. Under these conditions tosylphenylalanine chloromethyl ketone (Tos-PheCh2Cl) and tosyllysine chloromethyl ketone (Tos-LysCh2Cl) both almost completely inhibit the loss of tyrosine aminotransferase activity, implying the involvement of serine proteases in this process. Depletion of intracellular ATP levels to virtually zero also completely inhibits the apparent degradation of tyrosine aminotransferase. In contrast, the decline in ornithine decarboxylase activity following inhibition of protein synthesis is stimulated by both Tos-PheCH2Cl and Tos-LysCH2Cl, although with Tos-PheCH2Cl this stimulation is followed after 45 min by a complete inhibition of apparent degradation. ATP starvation inhibits the loss of ornithine decarboxylase activity by only 50%. © 1974.

Authors
McIlhinney, A; Hogan, BLM
MLA Citation
McIlhinney, A, and Hogan, BLM. "Effect of protease inhibitors on protein degradation in rat hepatoma cells II. Effects on ornithine decarboxylase and tyrosine aminotransferase." BBA - General Subjects 372.2 (1974): 366-373.
Source
scival
Published In
BBA - General Subjects
Volume
372
Issue
2
Publish Date
1974
Start Page
366
End Page
373

The induction of ornithine decarboxylase in cultured hepatoma cells.

Authors
Hogan, B; Blackledge, A
MLA Citation
Hogan, B, and Blackledge, A. "The induction of ornithine decarboxylase in cultured hepatoma cells." Biochemical Journal 130.2 (1972): 78P-79P.
PMID
4352432
Source
scival
Published In
Biochemical Journal
Volume
130
Issue
2
Publish Date
1972
Start Page
78P
End Page
79P

Nuclear RNA synthesis in sea urchin embryos

Nuclei have been prepared from sea urchin embryos at several stages of development, and the RNA isolated and characterized. Up to the swimming blastula stage, nuclear RNA labeled with 3H-uridine is dispersed throughout the nucleus and is not localized on any particular structure. It has a DNA-like base composition and is heterogeneous in size, most of it being larger than 26S. At stages in which large amounts of the 9S histone mRNA complex are synthesized and found on cytoplasmic polyribosomes, molecules of the same size and electrophoretic mobility cannot be detected in the nuclei. Nuclei from gastrulae contain easily identifiable 36S and 28S RNAs that precursors to mature ribosoml RNA (26S and 18S). Also present in these nuclei are homodisperse low molecular weight species of unknown function, previously observed only in the cells of warm-blooded animals. © 1972.

Authors
Hogan, B; Gross, PR
MLA Citation
Hogan, B, and Gross, PR. "Nuclear RNA synthesis in sea urchin embryos." Experimental Cell Research 72.1 (1972): 101-114.
PMID
4554434
Source
scival
Published In
Experimental Cell Research
Volume
72
Issue
1
Publish Date
1972
Start Page
101
End Page
114

Effect of growth conditions on the ornithine decarboxylase activity of rat hepatoma cells.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "Effect of growth conditions on the ornithine decarboxylase activity of rat hepatoma cells." Biochem Biophys Res Commun 45.2 (October 15, 1971): 301-307.
PMID
4400789
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
45
Issue
2
Publish Date
1971
Start Page
301
End Page
307

The effect of protein synthesis inhibition on the entry of messenger RNA into the cytoplasm of sea urchin embryos.

Authors
Hogan, B; Gross, PR
MLA Citation
Hogan, B, and Gross, PR. "The effect of protein synthesis inhibition on the entry of messenger RNA into the cytoplasm of sea urchin embryos." Journal of Cell Biology 49.3 (1971): 692-701.
PMID
4997172
Source
scival
Published In
Journal of Cell Biology
Volume
49
Issue
3
Publish Date
1971
Start Page
692
End Page
701

he effect of inhibitors of protein synthesis on the level of ribosomal subunits in ascites cells.

Authors
Hogan, BL
MLA Citation
Hogan, BL. "he effect of inhibitors of protein synthesis on the level of ribosomal subunits in ascites cells." Biochim Biophys Acta 182.1 (May 20, 1969): 264-266.
PMID
5792854
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
182
Issue
1
Publish Date
1969
Start Page
264
End Page
266

Regulation of translation and transcription of messenger RNA during early embryonic development.

Authors
Kedes, LH; Hogan, B; Cognetti, G; Selvig, S; Yanover, P; Gross, PR
MLA Citation
Kedes, LH, Hogan, B, Cognetti, G, Selvig, S, Yanover, P, and Gross, PR. "Regulation of translation and transcription of messenger RNA during early embryonic development." Cold Spring Harbor Symposia on Quantitative Biology 34 (1969): 717-723.
PMID
5266187
Source
scival
Published In
Cold Spring Harbor Symposia on Quantitative Biology
Volume
34
Publish Date
1969
Start Page
717
End Page
723

The effect of inhibitors of protein synthesis on the level of ribosomal subunits in ascites cells

Authors
Hogan, BLM
MLA Citation
Hogan, BLM. "The effect of inhibitors of protein synthesis on the level of ribosomal subunits in ascites cells." BBA Section Nucleic Acids And Protein Synthesis 182.1 (1969): 264-266.
Source
scival
Published In
Biochimica et Biophysica Acta - Section Nucleic Acids And Protein Synthesis
Volume
182
Issue
1
Publish Date
1969
Start Page
264
End Page
266

The role of ribosomal subunits and 80-S monomers in polysome formation in an ascites tumour cell.

Authors
Hogan, BL; Korner, A
MLA Citation
Hogan, BL, and Korner, A. "The role of ribosomal subunits and 80-S monomers in polysome formation in an ascites tumour cell." Biochim Biophys Acta 169.1 (November 20, 1968): 139-149.
PMID
5727128
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
169
Issue
1
Publish Date
1968
Start Page
139
End Page
149

Ribosomal subunits of Landschütz ascites cells during changes in polysome distribution.

Authors
Hogan, BL; Korner, A
MLA Citation
Hogan, BL, and Korner, A. "Ribosomal subunits of Landschütz ascites cells during changes in polysome distribution." Biochim Biophys Acta 169.1 (November 20, 1968): 129-138.
PMID
5727127
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
169
Issue
1
Publish Date
1968
Start Page
129
End Page
138
Show More

Research Areas:

  • 3T3 Cells
  • Abnormalities, Multiple
  • Acetyltransferases
  • Actins
  • Adenocarcinoma
  • Adult Stem Cells
  • Age of Onset
  • Aging
  • Alkaline Phosphatase
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  • Animals, Newborn
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  • Basic-Leucine Zipper Transcription Factors
  • Bioethics
  • Biological Evolution
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  • Blastocyst
  • Bleomycin
  • Blood Pressure
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  • Body Patterning
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  • Bone Morphogenetic Protein 1
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
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  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Protein Receptors
  • Bone Morphogenetic Protein Receptors, Type I
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  • Chloramphenicol O-Acetyltransferase
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