You are here

Kuo, Chay Titus

Overview:

We are interested in the regulation of postnatal/adult neural stem cells and how they modify brain homeostasis in health and disease. Throughout embryonic and postnatal development, neural stem cells give rise to differentiated neurons, astrocytes, and oligodendrocytes which modulate function of the adult nervous system. While during embryogenesis these progenitor cells are relatively abundant and help to construct the overall CNS architecture, during postnatal and adult periods they become restricted to specialized regions in the brain and produce progeny that participate in the modification of neural circuits and brain homeostasis. The work in my laboratory centers around understanding cellular pathways regulating postnatal/adult neural stem cells, using the rodent brain as a model system. Our current focus deals with how specialized environments in the brain (also called “niches”) sustain production of new neurons in vivo; how these microenvironments are changed in response to circuit-level inputs; and how injury modifies neural stem cell proliferation/differentiation. A better understanding of these processes may lead to future therapies for patients suffering from pre/postnatal brain injuries.

Positions:

Associate Professor of Cell Biology

Cell Biology
School of Medicine

Assistant Professor in Neurobiology

Neurobiology
School of Medicine

Assistant Professor of Pediatrics

Pediatrics, Neonatology
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1997

Ph.D. — University of Chicago

M.D. 2002

M.D. — University of Chicago

News:

Grants:

Molecular and cellular control of injury-induced astrogenesis

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2017
End Date
January 31, 2022

Integrated Training in Anesthesiology Research

Administered By
Anesthesiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1996
End Date
June 30, 2021

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

Control of Postnatal SVZ Neurogenesis via Cholinergic Circuit Activity

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
November 19, 2014
End Date
October 31, 2019

NINDS Research Education Programs for Residents and Fellows in Neurosurgery

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
March 01, 2009
End Date
June 30, 2019

Investigating the Molecular Mechanisms Regulating Brain Ventricular Wall Maturation

Administered By
Cell Biology
AwardedBy
March of Dimes
Role
Principal Investigator
Start Date
June 01, 2016
End Date
May 31, 2019

Ependymal control of new neuron production in the adult brain

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2012
End Date
February 28, 2018

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

Modulating newborn neuron intrinsic activity for functional integration after injury

Administered By
Cell Biology
AwardedBy
Ruth K. Broad Biomedical Research Foundation
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2017

Basic predoctoral training in neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 1992
End Date
June 30, 2017

Serial Block Face Scanning Electron Microscope

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Major User
Start Date
June 01, 2016
End Date
May 31, 2017

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

Thrombospondin-4 Function in Lateral Ventricular Astrogenesis and Cortical Repair after Stroke

Administered By
Cell Biology
AwardedBy
Ruth K. Broad Biomedical Research Foundation
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2016

Training in Fundamental &Translational Neuroscience

Administered By
Neurobiology
AwardedBy
National Institutes of Health
Role
Training Faculty
Start Date
July 01, 2005
End Date
February 29, 2016

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

Discovering pathways regulating neurogenesis and brain remodeling after injury

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2008
End Date
June 30, 2013

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010
Show More

Awards:

Sloan Research Fellowship-Neuroscience. Alfred P. Sloan Foundation.

Type
National
Awarded By
Alfred P. Sloan Foundation
Date
January 01, 2010

Fellowships for Science and Engineering. David and Lucile Packard Foundation.

Type
National
Awarded By
David and Lucile Packard Foundation
Date
January 01, 2008

Publications:

Identification of distinct ChAT⁺ neurons and activity-dependent control of postnatal SVZ neurogenesis.

Postnatal and adult subventricular zone (SVZ) neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular and niche-driven cues. Although behavioral experiments and disease states have suggested possibilities for higher level inputs, it is unknown whether neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We identified a previously unknown population of choline acetyltransferase (ChAT)(+) neurons residing in the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts and released acetylcholine locally in an activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT(+) neurons in vivo indicated that they were necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with fibroblast growth factor receptor activation to increase neuroblast production. These results reveal an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control and suggest possibilities for modulating neuroregenerative capacities in health and disease.

Authors
Paez-Gonzalez, P; Asrican, B; Rodriguez, E; Kuo, CT
MLA Citation
Paez-Gonzalez, P, Asrican, B, Rodriguez, E, and Kuo, CT. "Identification of distinct ChAT⁺ neurons and activity-dependent control of postnatal SVZ neurogenesis." Nature neuroscience 17.7 (July 2014): 934-942.
PMID
24880216
Source
epmc
Published In
Nature Neuroscience
Volume
17
Issue
7
Publish Date
2014
Start Page
934
End Page
942
DOI
10.1038/nn.3734

Cysteine proteinase-1 and cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron.

Dendrites often exhibit structural changes in response to local inputs. Although mechanisms that pattern and maintain dendritic arbors are becoming clearer, processes regulating regrowth, during context-dependent plasticity or after injury, remain poorly understood. We found that a class of Drosophila sensory neurons, through complete pruning and regeneration, can elaborate two distinct dendritic trees, innervating independent sensory fields. An expression screen identified Cysteine proteinase-1 (Cp1) as a critical regulator of this process. Unlike known ecdysone effectors, Cp1-mutant ddaC neurons pruned larval dendrites normally but failed to regrow adult dendrites. Cp1 expression was upregulated/concentrated in the nucleus during metamorphosis, controlling production of a truncated Cut homeodomain transcription factor. This truncated Cut, but not the full-length protein, allowed Cp1-mutant ddaC neurons to regenerate higher-order adult dendrites. These results identify a molecular pathway needed for dendrite regrowth after pruning, which allows the same neuron to innervate distinct sensory fields.

Authors
Lyons, GR; Andersen, RO; Abdi, K; Song, W-S; Kuo, CT
MLA Citation
Lyons, GR, Andersen, RO, Abdi, K, Song, W-S, and Kuo, CT. "Cysteine proteinase-1 and cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron." Cell reports 6.5 (March 2014): 783-791.
Website
http://hdl.handle.net/10161/8375
PMID
24582961
Source
epmc
Published In
Cell Reports
Volume
6
Issue
5
Publish Date
2014
Start Page
783
End Page
791
DOI
10.1016/j.celrep.2014.02.003

Cysteine Proteinase-1 and Cut Protein Isoform Control Dendritic Innervation of Two Distinct Sensory Fields by a Single Neuron

Authors
Lyons, GR; Andersen, RO; Abdi, K; Song, W-S; Kuo, CT
MLA Citation
Lyons, GR, Andersen, RO, Abdi, K, Song, W-S, and Kuo, CT. "Cysteine Proteinase-1 and Cut Protein Isoform Control Dendritic Innervation of Two Distinct Sensory Fields by a Single Neuron." Cell Reports 6.5 (March 2014): 783-791.
Source
crossref
Published In
Cell Reports
Volume
6
Issue
5
Publish Date
2014
Start Page
783
End Page
791
DOI
10.1016/j.celrep.2014.02.003

Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis

Postnatal and adult subventricular zone (SVZ) neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular and niche-driven cues. Although behavioral experiments and disease states have suggested possibilities for higher level inputs, it is unknown whether neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We identified a previously unknown population of choline acetyltransferase (ChAT)+ neurons residing in the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts and released acetylcholine locally in an activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT+ neurons in vivo indicated that they were necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with fibroblast growth factor receptor activation to increase neuroblast production. These results reveal an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control and suggest possibilities for modulating neuroregenerative capacities in health and disease. © 2014 Nature America, Inc. All rights reserved.

Authors
Paez-Gonzalez, P; Asrican, B; Rodriguez, E; Kuo, CT
MLA Citation
Paez-Gonzalez, P, Asrican, B, Rodriguez, E, and Kuo, CT. "Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis." Nature Neuroscience 17.7 (January 1, 2014): 934-942.
Source
scopus
Published In
Nature Neuroscience
Volume
17
Issue
7
Publish Date
2014
Start Page
934
End Page
942
DOI
10.1038/nn.3734

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

Authors
Wang, W; Pan, Y-W; Wietecha, T; Zou, J; Abel, GM; Kuo, CT; Xia, Z
MLA Citation
Wang, W, Pan, Y-W, Wietecha, T, Zou, J, Abel, GM, Kuo, CT, and Xia, Z. "Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb." JOURNAL OF BIOLOGICAL CHEMISTRY 288.4 (January 25, 2013): 2623-2631.
PMID
23223235
Source
wos-lite
Published In
The Journal of biological chemistry
Volume
288
Issue
4
Publish Date
2013
Start Page
2623
End Page
2631
DOI
10.1074/jbc.M112.401091

Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4

Postnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ; also called subependymal zone) generate doublecortin (Dcx) + neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing the neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear whether there are conditions that favour astrogenesis over neurogenesis in the SVZ niche, and whether astrocytes produced there have different properties compared with astrocytes produced elsewhere in the brain. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical injury initiates a marked increase in Thbs4 hi astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creER tm 4 lineage tracing demonstrated that it is these SVZ-generated Thbs4 hi astrocytes, and not Dcx + neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4 KO/KO) showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing cells expressing Dcx migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular haemorrhage into the brain parenchyma of Thbs4 KO/KO mice. Taken together, these findings have important implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles. © 2013 Macmillan Publishers Limited. All rights reserved.

Authors
Benner, EJ; Luciano, D; Jo, R; Abdi, K; Paez-Gonzalez, P; Sheng, H; Warner, DS; Liu, C; Eroglu, C; Kuo, CT
MLA Citation
Benner, EJ, Luciano, D, Jo, R, Abdi, K, Paez-Gonzalez, P, Sheng, H, Warner, DS, Liu, C, Eroglu, C, and Kuo, CT. "Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4." Nature 497.7449 (2013): 369-373.
Source
scival
Published In
Nature
Volume
497
Issue
7449
Publish Date
2013
Start Page
369
End Page
373
DOI
10.1038/nature12069

Inducible and Targeted Deletion of the ERK5 MAP Kinase in Adult Neurogenic Regions Impairs Adult Neurogenesis in the Olfactory Bulb and Several Forms of Olfactory Behavior

Although adult-born neurons in the subventricular zone (SVZ) and olfactory bulb (OB) have been extensively characterized at the cellular level, their functional impact on olfactory behavior is still highly controversial with many conflicting results reported in the literature. Furthermore, signaling mechanisms regulating adult SVZ/OB neurogenesis are not well defined. Here we report that inducible and targeted deletion of erk5, a MAP kinase selectively expressed in the adult neurogenic regions of the adult brain, impairs adult neurogenesis in the SVZ and OB of transgenic mice. Although erk5 deletion had no effect on olfactory discrimination among discrete odorants in the habituation/dishabituation assay, it reduced short-term olfactory memory as well as detection sensitivity to odorants and pheromones including those evoking aggression and fear. Furthermore, these mice show impaired acquisition of odor-cued associative olfactory learning, a novel phenotype that had not been previously linked to adult neurogenesis. These data suggest that ERK5 MAP kinase is a critical kinase signaling pathway regulating adult neurogenesis in the SVZ/OB, and provide strong evidence supporting a functional role for adult neurogenesis in several distinct forms of olfactory behavior. © 2012 Pan et al.

Authors
Pan, Y-W; Kuo, CT; Storm, DR; Xia, Z
MLA Citation
Pan, Y-W, Kuo, CT, Storm, DR, and Xia, Z. "Inducible and Targeted Deletion of the ERK5 MAP Kinase in Adult Neurogenic Regions Impairs Adult Neurogenesis in the Olfactory Bulb and Several Forms of Olfactory Behavior." PLoS ONE 7.11 (2012).
PMID
23185386
Source
scival
Published In
PloS one
Volume
7
Issue
11
Publish Date
2012
DOI
10.1371/journal.pone.0049622

Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory

Although there is evidence suggesting that adult neurogenesis may contribute to hippocampus-dependent memory, signaling mechanisms responsible for adult hippocampal neurogenesis are not well characterized. Here we report that ERK5 mitogen-activated protein kinase is specifically expressed in the neurogenic regions of the adult mouse brain. The inducible and conditional knock-out (icKO) of erk5 specifically in neural progenitors of the adult mouse brain attenuated adult hippocampal neurogenesis. It also caused deficits in several forms of hippocampus-dependent memory, including contextual fear conditioning generated by a weak footshock. The ERK5 icKO mice were also deficient in contextual fear extinction and reversal of Morris water maze spatial learning and memory, suggesting that adult neurogenesis plays an important role in hippocampus-dependent learning flexibility. Furthermore, our data suggest a critical role for ERK5-mediated adult neurogenesis in pattern separation, a form of dentate gyrus-dependent spatial learning and memory. Moreover, ERK5 icKO mice have no memory 21 d after training in the passive avoidance test, suggesting a pivotal role for adult hippocampal neurogenesis in the expression of remote memory. Together, our results implicate ERK5 as a novel signaling molecule regulating adult neurogenesis and provide strong evidence that adult neurogenesis is critical for several forms of hippocampus-dependent memory formation, including fear extinction, and for the expression of remote memory. © 2012 the authors.

Authors
Pan, Y-W; Chan, GCK; Kuo, CT; Storm, DR; Xia, Z
MLA Citation
Pan, Y-W, Chan, GCK, Kuo, CT, Storm, DR, and Xia, Z. "Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory." Journal of Neuroscience 32.19 (2012): 6444-6455.
PMID
22573667
Source
scival
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
32
Issue
19
Publish Date
2012
Start Page
6444
End Page
6455
DOI
10.1523/JNEUROSCI.6076-11.2012

Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis

Recent studies have led to the exciting idea that adult-born neurons in the dentate gyrus of the hippocampus may play a role in hippocampus-dependent memory formation. However, signaling mechanisms that regulate adult hippocampal neurogenesis are not well defined. Here we report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, is selectively expressed in the neurogenic regions of the adult mouse brain.We present evidence that shRNA suppression of ERK5 in adult hippocampal neural stem/progenitor cells (aNPCs) reduces the number of neurons while increasing the number of cells expressing markers for stem/progenitor cells or proliferation. Furthermore, shERK5 attenuates both transcription and neuronal differentiation mediated by Neurogenin 2, a transcription factor expressed in adult hippocampal neural progenitor cells. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, promotes neurogenesis in cultured aNPCs and in the dentate gyrus of the mouse brain. Moreover, neurotrophins including NT3 activate ERK5 and stimulate neuronal differentiation in aNPCs in an ERK5-dependent manner. Finally, inducible and conditional deletion of ERK5 specifically in the neurogenic regions of the adult mouse brain delays the normal progression of neuronal differentiation and attenuates adult neurogenesis in vivo. These data suggest ERK5 signaling as a critical regulator of adult hippocampal neurogenesis. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Pan, Y-W; Zou, J; Wang, W; Sakagami, H; Garelick, MG; Abel, G; Kuo, CT; Storm, DR; Xia, Z
MLA Citation
Pan, Y-W, Zou, J, Wang, W, Sakagami, H, Garelick, MG, Abel, G, Kuo, CT, Storm, DR, and Xia, Z. "Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis." Journal of Biological Chemistry 287.28 (2012): 23306-23317.
PMID
22645146
Source
scival
Published In
The Journal of biological chemistry
Volume
287
Issue
28
Publish Date
2012
Start Page
23306
End Page
23317
DOI
10.1074/jbc.M112.344762

Ank3-dependent SVZ niche assembly is required for the continued production of new neurons.

The rodent subventricular/subependymal zone (SVZ/SEZ) houses neural stem cells (NSCs) that generate olfactory bulb interneurons. It is unclear how the SVZ environment sustains neuronal production into adulthood. We discovered that the adapter molecule Ankyrin-3 (Ank3) is specifically upregulated in ventricular progenitors destined to become ependymal cells, but not in NSCs, and is required for SVZ niche assembly through progenitor lateral adhesion. Furthermore, we found that Ank3 expression is controlled by Foxj1, a transcriptional regulator of multicilia formation, and genetic deletion of this pathway led to complete loss of SVZ niche structure. Interestingly, radial glia continued to transition into postnatal NSCs without this niche. However, inducible deletion of Foxj1-Ank3 from mature SVZ ependyma resulted in dramatic depletion of neurogenesis. Targeting a pathway regulating ependymal organization/assembly and showing its requirement for new neuron production, our results have important implications for environmental control of adult neurogenesis and harvesting NSCs for replacement therapy.

Authors
Paez-Gonzalez, P; Abdi, K; Luciano, D; Liu, Y; Soriano-Navarro, M; Rawlins, E; Bennett, V; Garcia-Verdugo, JM; Kuo, CT
MLA Citation
Paez-Gonzalez, P, Abdi, K, Luciano, D, Liu, Y, Soriano-Navarro, M, Rawlins, E, Bennett, V, Garcia-Verdugo, JM, and Kuo, CT. "Ank3-dependent SVZ niche assembly is required for the continued production of new neurons." Neuron 71.1 (July 14, 2011): 61-75.
PMID
21745638
Source
pubmed
Published In
Neuron
Volume
71
Issue
1
Publish Date
2011
Start Page
61
End Page
75
DOI
10.1016/j.neuron.2011.05.029

POSTNATAL STEM-CELL NICHE ASSEMBLY IS CRITICAL FOR CONTINUED ASTROCYTE VS NEUROBLAST PRODUCTION

Authors
Paez-Gonalez, P; Abdi, K; Luciano, D; Liu, Y; Kuo, CT
MLA Citation
Paez-Gonalez, P, Abdi, K, Luciano, D, Liu, Y, and Kuo, CT. "POSTNATAL STEM-CELL NICHE ASSEMBLY IS CRITICAL FOR CONTINUED ASTROCYTE VS NEUROBLAST PRODUCTION." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I34
End Page
I34

Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche.

Neural stem cells are retained in the postnatal subventricular zone (SVZ), a specialized neurogenic niche with unique cytoarchitecture and cell-cell contacts. Although the SVZ stem cells continuously regenerate, how they and the niche respond to local changes is unclear. Here we generated nestin-creER(tm) transgenic mice with inducible Cre recombinase in the SVZ and removed Numb/Numblike, key regulators of embryonic neurogenesis from postnatal SVZ progenitors and ependymal cells. This resulted in severe damage to brain lateral ventricle integrity and identified roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival. Surprisingly, the ventricular damage was eventually repaired: SVZ reconstitution and ventricular wall remodeling were mediated by progenitors that escaped Numb deletion. Our results show a self-repair mechanism in the mammalian brain and may have implications for both niche plasticity in other areas of stem cell biology and the therapeutic use of neural stem cells in neurodegenerative diseases.

Authors
Kuo, CT; Mirzadeh, Z; Soriano-Navarro, M; Rasin, M; Wang, D; Shen, J; Sestan, N; Garcia-Verdugo, J; Alvarez-Buylla, A; Jan, LY; Jan, Y-N
MLA Citation
Kuo, CT, Mirzadeh, Z, Soriano-Navarro, M, Rasin, M, Wang, D, Shen, J, Sestan, N, Garcia-Verdugo, J, Alvarez-Buylla, A, Jan, LY, and Jan, Y-N. "Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche." Cell 127.6 (December 15, 2006): 1253-1264.
PMID
17174898
Source
pubmed
Published In
Cell
Volume
127
Issue
6
Publish Date
2006
Start Page
1253
End Page
1264
DOI
10.1016/j.cell.2006.10.041

Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning.

Ubiquitin-proteasome system (UPS) is a multistep protein degradation machinery implicated in many diseases. In the nervous system, UPS regulates remodeling and degradation of neuronal processes and is linked to Wallerian axonal degeneration, though the ubiquitin ligases that confer substrate specificity remain unknown. Having shown previously that class IV dendritic arborization (C4da) sensory neurons in Drosophila undergo UPS-mediated dendritic pruning during metamorphosis, we conducted an E2/E3 ubiquitinating enzyme mutant screen, revealing that mutation in ubcD1, an E2 ubiquitin-conjugating enzyme, resulted in retention of C4da neuron dendrites during metamorphosis. Further, we found that UPS activation likely leads to UbcD1-mediated degradation of DIAP1, a caspase-antagonizing E3 ligase. This allows for local activation of the Dronc caspase, thereby preserving C4da neurons while severing their dendrites. Thus, in addition to uncovering E2/E3 ubiquitinating enzymes for dendrite pruning, this study provides a mechanistic link between UPS and the apoptotic machinery in regulating neuronal process remodeling.

Authors
Kuo, CT; Zhu, S; Younger, S; Jan, LY; Jan, YN
MLA Citation
Kuo, CT, Zhu, S, Younger, S, Jan, LY, and Jan, YN. "Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning." Neuron 51.3 (August 3, 2006): 283-290.
PMID
16880123
Source
pubmed
Published In
Neuron
Volume
51
Issue
3
Publish Date
2006
Start Page
283
End Page
290
DOI
10.1016/j.neuron.2006.07.014

Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology.

Asymmetric cell division is an evolutionarily conserved mechanism widely used to generate cellular diversity during development. Drosophila neuroblasts have been a useful model system for studying the molecular mechanisms of asymmetric cell division. In this minireview, we focus on recent progress in understanding the role of heterotrimeric G proteins and their regulators in asymmetric spindle geometry, as well as the role of an Inscuteable-independent microtubule pathway in asymmetric localization of proteins in neuroblasts. We also discuss issues of progenitor proliferation and differentiation associated with asymmetric cell division and their broader implications for stem cell biology.

Authors
Yu, F; Kuo, CT; Jan, YN
MLA Citation
Yu, F, Kuo, CT, and Jan, YN. "Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology." Neuron 51.1 (July 6, 2006): 13-20. (Review)
PMID
16815328
Source
pubmed
Published In
Neuron
Volume
51
Issue
1
Publish Date
2006
Start Page
13
End Page
20
DOI
10.1016/j.neuron.2006.06.016

Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling.

During neuronal maturation, dendrites develop from immature neurites into mature arbors. In response to changes in the environment, dendrites from certain mature neurons can undergo large-scale morphologic remodeling. Here, we show a group of Drosophila peripheral sensory neurons, the class IV dendritic arborization (C4da) neurons, that completely degrade and regrow their elaborate dendrites. Larval dendrites of C4da neurons are first severed from the soma and subsequently degraded during metamorphosis. This process is controlled by both intracellular and extracellular mechanisms: The ecdysone pathway and ubiquitin-proteasome system (UPS) are cell-intrinsic signals that initiate dendrite breakage, and extracellular matrix metalloproteases are required to degrade the severed dendrites. Surprisingly, C4da neurons retain their axonal projections during concurrent dendrite degradation, despite activated ecdysone and UPS pathways. These results demonstrate that, in response to environmental changes, certain neurons have cell-intrinsic abilities to completely lose their dendrites but keep their axons and subsequently regrow their dendritic arbors.

Authors
Kuo, CT; Jan, LY; Jan, YN
MLA Citation
Kuo, CT, Jan, LY, and Jan, YN. "Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling." Proc Natl Acad Sci U S A 102.42 (October 18, 2005): 15230-15235.
PMID
16210248
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
102
Issue
42
Publish Date
2005
Start Page
15230
End Page
15235
DOI
10.1073/pnas.0507393102

The hand that rocks the spindle.

Authors
Kuo, CT; Jan, Y-N
MLA Citation
Kuo, CT, and Jan, Y-N. "The hand that rocks the spindle." Nat Cell Biol 7.9 (September 2005): 858-859.
PMID
16136185
Source
pubmed
Published In
Nature Cell Biology
Volume
7
Issue
9
Publish Date
2005
Start Page
858
End Page
859
DOI
10.1038/ncb0905-858

The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4

Resistance to the stimulatory effects of insulin on glucose utilization is a key feature of type 2 diabetes, obesity, and the metabolic syndrome. Recent studies suggest that insulin resistance is primarily caused by a defect in glucose transport. GLUT4 is the main insulin-responsive glucose transporter and is expressed predominantly in muscle and adipose tissues. Whereas GLUT4 has been shown to play a critical role in maintaining systemic glucose homeostasis, the mechanisms regulating its expression are incompletely understood. We have cloned the murine homologue of KLF15, a member of the Krüppel-like family of transcription factors. KLF15 is highly expressed in adipocytes and myocytes in vivo and is induced when 3T3-L1 preadipocytes are differentiated into adipocytes. Overexpression of KLF15 in adipose and muscle cell lines potently induces GLUT4 expression. This effect is specific to KLF15 as overexpression of two other Krüppel-like factors, KLF2/LKLF and KLF4/GKLF, did not induce GLUT4 expression. Both basal (3.3-fold, p < 0.001) and insulin-stimulated (2.4-fold, p < 0.00001) glucose uptake are increased in KLF15- overexpressing adipocytes. In co-transfection assays, KLF15 and MEF2X a known activator of GLUT4, synergistically activates the GLUT4 promoter. Promoter deletion and mutational analyses provide evidence that this activity requires an intact KLF15-binding site proximal to the MEF2A site. Finally, co-immunoprecipitation assays show that KLF15 specifically interacts with MEF2A. These studies indicate that KLF15 is an important regulator of GLUT4 in both adipose and muscle tissues.

Authors
Gray, S; Feinberg, MW; Hull, S; Kuo, CT; Watanabe, M; Sen, S; Depina, A; Haspel, R; Jain, MK
MLA Citation
Gray, S, Feinberg, MW, Hull, S, Kuo, CT, Watanabe, M, Sen, S, Depina, A, Haspel, R, and Jain, MK. "The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4." Journal of Biological Chemistry 277.37 (2002): 34322-34328.
PMID
12097321
Source
scival
Published In
The Journal of biological chemistry
Volume
277
Issue
37
Publish Date
2002
Start Page
34322
End Page
34328
DOI
10.1074/jbc.M201304200

Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway.

T lymphocytes circulate in a quiescent state until they encounter cognate antigen bound to the surface of an antigen-presenting cell. The molecular pathways that regulate T cell quiescence remain largely unknown. Here we show that forced expression of the lung Krüppel-like transcription factor (LKLF) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation, reduced cell size and protein synthesis and decreased surface expression of activation markers. Conversely, LKLF-deficient peripheral T cells produced by gene targeting showed increased proliferation, increased cell size and enhanced expression of surface activation markers in vivo. LKLF appeared to function, at least in part, by decreasing expression of the proto-oncogene encoding c-Myc. Forced expression of LKLF was associated with markedly decreased c-Myc expression. In addition, many effects of LKLF expression were mimicked by expression of the dominant-negative MadMyc protein and rescued by overexpression of c-Myc. Thus, LKLF is both necessary and sufficient to program quiescence in T cells and functions, in part, by negatively regulating a c-Myc--dependent pathway.

Authors
Buckley, AF; Kuo, CT; Leiden, JM
MLA Citation
Buckley, AF, Kuo, CT, and Leiden, JM. "Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway." Nat Immunol 2.8 (August 2001): 698-704.
PMID
11477405
Source
pubmed
Published In
Nature Immunology
Volume
2
Issue
8
Publish Date
2001
Start Page
698
End Page
704
DOI
10.1038/90633

Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus.

BATF belongs to the AP-1/ATF superfamily of transcription factors and forms heterodimers with Jun proteins to bind AP-1 consensus DNA. Unlike Fos/Jun heterodimers which stimulate gene transcription, BATF/Jun heterodimers are transcriptionally inert and inhibit biological processes that are associated with the overstimulation of AP-1 activity. Here, we describe the murine BATF cDNA and genomic clones and map the BATF locus to chromosome 12 D2-3. Using in situ hybridization of BATF mRNA, we show that BATF gene expression is highly restricted, with the most prominent signals detected in the thymus. BATF mRNA levels are regulated differentially during discrete stages of T cell development and are up-regulated following activation of T cells in the periphery. To demonstrate the impact of BATF on AP-1 activity in vivo, AP-1 luciferase reporter mice were crossed to transgenic mice overexpressing BATF exclusively in thymic T cells. Results show that elevated levels of BATF protein correlate with reduced transactivation by AP-1. Since the differential regulation of AP-1 activity is linked to key transitions in the developing immune system, our observations support a critical role for BATF in determining the overall level of AP-1 activity, and thus AP-1 target gene expression, in specific T cell subtypes.

Authors
Williams, KL; Nanda, I; Lyons, GE; Kuo, CT; Schmid, M; Leiden, JM; Kaplan, MH; Taparowsky, EJ
MLA Citation
Williams, KL, Nanda, I, Lyons, GE, Kuo, CT, Schmid, M, Leiden, JM, Kaplan, MH, and Taparowsky, EJ. "Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus." European journal of immunology 31.5 (May 2001): 1620-1627.
PMID
11466704
Source
epmc
Published In
European Journal of Immunology
Volume
31
Issue
5
Publish Date
2001
Start Page
1620
End Page
1627
DOI
10.1002/1521-4141(200105)31:5<1620::aid-immu1620>3.0.co;2-3

Characterization of murine BATF: A negative regulator of activator protein-1 activity in the thymus

BATF belongs to the AP-1/ATF superfamily of transcription factors and forms heterodimers with Jun proteins to bind AP-1 consensus DNA. Unlike Fos/Jun heterodimers which stimulate gene transcription, BATF/Jun heterodimers are transcriptionally inert and inhibit biological processes that are associated with the overstimulation of AP-1 activity. Here, we describe the murine BATF cDNA and genomic clones and map the BATF locus to chromosome 12 D2-3. Using in situ hybridization of BATF mRNA, we show that BATF gene expression is highly restricted, with the most prominent signals detected in the thymus. BATF mRNA levels are regulated differentially during discrete stages of T cell development and are up-regulated following activation of T cells in the periphery. To demonstrate the impact of BATF on AP-1 activity in vivo, AP-1 luciferase reporter mice were crossed to transgenic mice overexpressing BATF exclusively in thymic T cells. Results show that elevated levels of BATF protein correlate with reduced transactivation by AP-1. Since the differential regulation of AP-1 activity is linked to key transitions in the developing immune system, our observations support a critical role for BATF in determining the overall level of AP-1 activity, and thus AP-1 target gene expression, in specific T cell subtypes.

Authors
Williams, KL; Nanda, I; Lyons, GE; Kuo, CT; Schmid, M; Leiden, JM; Kaplan, MH; Taparowsky, EJ
MLA Citation
Williams, KL, Nanda, I, Lyons, GE, Kuo, CT, Schmid, M, Leiden, JM, Kaplan, MH, and Taparowsky, EJ. "Characterization of murine BATF: A negative regulator of activator protein-1 activity in the thymus." European Journal of Immunology 31.5 (2001): 1620-1627.
Source
scival
Published In
European Journal of Immunology
Volume
31
Issue
5
Publish Date
2001
Start Page
1620
End Page
1627
DOI
10.1002/1521-4141(200105)31:5<1620::AID-IMMU1620>3.0.CO;2-3

Transcriptional regulation of T lymphocyte development and function

The development and function of T lymphocytes are regulated tightly by signal transduction pathways that include specific cell-surface receptors, intracellular signaling molecules, and nuclear transcription factors. Since 1988, several families of functionally important T cell transcription factors have been identified. These include the Ikaros, LKLF, and GATA3 zinc-finger proteins; the Ets, CREB/ATF, and NF-κB/Rel/NFAT transcription factors; the Stat proteins; and HMG box transcription factors such as LEF1, TCF1, and Sox4. In this review, we summarize our current understanding of the transcriptional regulation of T cell development and function with particular emphasis on the results of recent gene targeting and transgenic experiments. In addition to increasing our understanding of the molecular pathways that regulate T cell development and function, these results have suggested novel targets for genetic and pharmacological manipulation of T cell immunity.

Authors
Kuo, CT; Leiden, JM
MLA Citation
Kuo, CT, and Leiden, JM. "Transcriptional regulation of T lymphocyte development and function." Annual Review of Immunology 17 (1999): 149-187.
PMID
10358756
Source
scival
Published In
Annual Review of Immunology
Volume
17
Publish Date
1999
Start Page
149
End Page
187
DOI
10.1146/annurev.immunol.17.1.149

Expression of the transcription factor lung Kruppel-like factor is regulated by cytokines and correlates with survival memory T cells in vitro and in vivo

The transcription factor lung Kruppel-like factor (LKLF) is involved in naive T cell survival. Expression of LKLF is rapidly down-regulated upon T cell stimulation, raising the question of whether LKLF is reexpressed after activation, and what factors are required for such reexpression. Furthermore, the expression of LKLF in resting memory cells has not been determined. Here, we use the OT-I TCR transgenic mouse system to address these issues. LKLF was found to be reexpressed following culture of activated CD8 T cells in certain cytokines (IL-2, IL-7) but not others (IL-12) known to influence CTL development. Interestingly, induction of LKLF reexpression corresponded with long-term T cell survival and development of memory T cell phenotype. Furthermore, using OT-I cells stimulated in vivo, we demonstrated that Ag induced rapid LKLF down-regulation and that the factor is expressed by in vivo-derived memory T cells.

Authors
Schober, SL; Kuo, CT; Schluns, KS; Lefrancois, L; Leiden, JM; Jameson, SC
MLA Citation
Schober, SL, Kuo, CT, Schluns, KS, Lefrancois, L, Leiden, JM, and Jameson, SC. "Expression of the transcription factor lung Kruppel-like factor is regulated by cytokines and correlates with survival memory T cells in vitro and in vivo." Journal of Immunology 163.7 (1999): 3662-3667.
PMID
10490960
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
163
Issue
7
Publish Date
1999
Start Page
3662
End Page
3667

LKLF: A transcriptional regulator of single-positive T cell quiescence and survival

Mature single-positive (SP) T lymphocytes enter a 'resting' state in which they are proliferatively quiescent and relatively resistant to apoptosis. The molecular mechanisms regulating this quiescent phenotype were unknown. Here it was found that the expression of a Kruppel-like zinc finger transcription factor, lung Kruppel-like factor (LKLF), is developmentally induced during the maturation of SP quiescent T cells and rapidly extinguished after SP T cell activation. LKLF-deficient T cells produced by gene targeting had a spontaneously activated phenotype and died in the spleen and lymph nodes from Fas ligand-induced apoptosis. Thus, LKLF is required to program the quiescent state of SP T cells and to maintain their viability in the peripheral lymphoid organs and blood.

Authors
Kuo, CT; Veselits, ML; Leiden, JM
MLA Citation
Kuo, CT, Veselits, ML, and Leiden, JM. "LKLF: A transcriptional regulator of single-positive T cell quiescence and survival." Science 277.5334 (1997): 1986-1990.
PMID
9302292
Source
scival
Published In
Science
Volume
277
Issue
5334
Publish Date
1997
Start Page
1986
End Page
1990
DOI
10.1126/science.277.5334.1986

The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis

The transcriptional programs that regulate blood vessel formation are largely unknown. In this paper, we examine the role of the zinc finger transcription factor LKLF in murine blood vessel morphogenesis and homeostasis. By in situ hybridization and immunohistochemistry, we show that LKLF is expressed as early as embryonic day 9.5 (E9.5) in vascular endothelial cells throughout the developing mouse embryo. To better understand the function of LKLF, we used homologous recombination in embryonic stern (ES) cells to generate LKLF-deficient (LKLF(-/-)) mice. Both angiogenesis and vasculogenesis were normal in the LKLF(-/-) mice. However, LKLF(-/-) embryos died between E12.5 and E14.5 from severe intra-embryonic and intra-amniotic hemorrhaging. This bleeding disorder was associated with specific defects in blood vessel morphology. Umbilical veins and arteries in the LKLF(-/-) embryos displayed an abnormally thin tunica media and aneurysmal dilatation before rupturing into the amniotic cavity. Similarly, vascular smooth muscle cells in the aortae from the LKLF(-1-) animals displayed a cuboidal morphology and failed to organize into a compact tunica media. Consistent with these findings, electron microscopic analyses demonstrated endothelial call necrosis, significant reductions in the number of vessel-wall pericytes and differentiating smooth muscle cells, and decreased deposition of extracellular matrix in the LKLF(-/-) vessels. Despite these defects, in situ hybridization demonstrated normal expression of platelet-derived growth factor B, Tie1, Tie2, transforming growth factor β, and heparin-binding epidermal growth factor in the vasculature of the LKLF(-/-) embryos. Therefore, LKLF defines a novel transcriptional pathway in which endothelial cells regulate the assembly of the vascular tunica media and concomitant vessel wall stabilization during mammalian embryogenesis.

Authors
Kuo, CT; Veselits, ML; Barton, KP; Lu, MM; Clendenin, C; Leiden, JM
MLA Citation
Kuo, CT, Veselits, ML, Barton, KP, Lu, MM, Clendenin, C, and Leiden, JM. "The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis." Genes and Development 11.22 (1997): 2996-3006.
PMID
9367982
Source
scival
Published In
Genes & development
Volume
11
Issue
22
Publish Date
1997
Start Page
2996
End Page
3006

GATA4 transcription factor is required for ventral morphogenesis and heart tube formation

Previous studies have suggested that the GATA4 transcription factor plays an important role in regulating mammalian cardiac development. In the studies described in this report we have used gene targeting to produce GATA4-deficient mice. Homozygous GATA4-deficient (GATA4-1-) mice died between 8.5 and 10.5 days post coitum (dpc). GATA4-1- embryos displayed severe defects in both rostral-to-caudal and lateral-to-ventral folding, which were reflected in a generalized disruption of the ventral body pattern. This resulted in the defective formation of an organized foregut and anterior intestinal pore, the failure to close both the amniotic cavity and yolk sac, and the uniform lack of a ventral pericardial cavity and heart tube. Analysis of cardiac development in the GATA4-1- mice demonstrated that these embryos developed splanchnic mesoderm, which differentiated into primitive cardiac myocytes that expressed contractile proteins. However, consistent with the observed defect in ventral morphogenesis, these GATA4 -1- procardiomyocytes failed to migrate to the ventral midline to form a linear heart tube and instead formed aberrant cardiac structures in the anterior and dorsolateral regions of the embryo. The defect in ventral migration of the GATA4-1- procardiomyocytes was not cell intrinsic because GATA4-1- cardiac myocytes and endocardial cells populated the hearts of GATA-1- - C57BL/6 chimeric mice. Taken together, these results demonstrated that GATA4 is not essential for the specification of the cardiac cell lineages. However, they define a critical role for GATA4 in regulating the rostral-to-caudal and lateral-to-ventral folding of the embryo that is needed for normal cardiac morphogenesis.

Authors
Kuo, CT; Morrisey, EE; Anandappa, R; Sigrist, K; Lu, MM; Parmacek, MS; Soudais, C; Leiden, JM
MLA Citation
Kuo, CT, Morrisey, EE, Anandappa, R, Sigrist, K, Lu, MM, Parmacek, MS, Soudais, C, and Leiden, JM. "GATA4 transcription factor is required for ventral morphogenesis and heart tube formation." Genes and Development 11.8 (1997): 1048-1060.
PMID
9136932
Source
scival
Published In
Genes & development
Volume
11
Issue
8
Publish Date
1997
Start Page
1048
End Page
1060
Show More