Chay Kuo

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

Associate Professor in Neurobiology

Neurobiology
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

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

Ph.D. 1997

The University of Chicago

M.D. 2002

The University of Chicago

Grants:

Molecular control of ependymal cell plasticity and its contribution to new neuron production in the mammalian brain

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Molecular and cellular control of injury-induced astrogenesis

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Control of Postnatal SVZ Neurogenesis via Cholinergic Circuit Activity

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Investigating the Molecular Mechanisms Regulating Brain Ventricular Wall Maturation

Administered By
Cell Biology
Awarded By
March of Dimes
Role
Principal Investigator
Start Date
End Date

Modulating newborn neuron intrinsic activity for functional integration after injury

Administered By
Cell Biology
Awarded By
Ruth K. Broad Biomedical Research Foundation
Role
Principal Investigator
Start Date
End Date

Publications:

EGFR Signaling Termination via Numb Trafficking in Ependymal Progenitors Controls Postnatal Neurogenic Niche Differentiation.

Specialized microenvironments, called niches, control adult stem cell proliferation and differentiation. The brain lateral ventricular (LV) neurogenic niche is generated from distinct postnatal radial glial progenitors (pRGPs), giving rise to adult neural stem cells (NSCs) and niche ependymal cells (ECs). Cellular-intrinsic programs govern stem versus supporting cell maturation during adult niche assembly, but how they are differentially initiated within a similar microenvironment remains unknown. Using chemical approaches, we discovered that EGFR signaling powerfully inhibits EC differentiation by suppressing multiciliogenesis. We found that EC pRGPs actively terminated EGF activation through receptor redistribution away from CSF-contacting apical domains and that randomized EGFR membrane targeting blocked EC differentiation. Mechanistically, we uncovered spatiotemporal interactions between EGFR and endocytic adaptor protein Numb. Ca2+-dependent basolateral targeting of Numb is necessary and sufficient for proper EGFR redistribution. These results reveal a previously unknown cellular mechanism for neighboring progenitors to differentially engage environmental signals, initiating adult stem cell niche assembly.
Authors
Abdi, K; Neves, G; Pyun, J; Kiziltug, E; Ahrens, A; Kuo, CT
MLA Citation
Abdi, Khadar, et al. “EGFR Signaling Termination via Numb Trafficking in Ependymal Progenitors Controls Postnatal Neurogenic Niche Differentiation.Cell Rep, vol. 28, no. 8, Aug. 2019, pp. 2012-2022.e4. Pubmed, doi:10.1016/j.celrep.2019.07.056.
URI
https://scholars.duke.edu/individual/pub1404802
PMID
31433979
Source
pubmed
Published In
Cell Reports
Volume
28
Published Date
Start Page
2012
End Page
2022.e4
DOI
10.1016/j.celrep.2019.07.056

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.
Authors
Pan, Y-W; Zou, J; Wang, W; Sakagami, H; Garelick, MG; Abel, G; Kuo, CT; Storm, DR; Xia, Z
MLA Citation
Pan, Yung-Wei, et al. “Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis.J Biol Chem, vol. 287, no. 28, July 2012, pp. 23306–17. Pubmed, doi:10.1074/jbc.M112.344762.
URI
https://scholars.duke.edu/individual/pub782378
PMID
22645146
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
287
Published Date
Start Page
23306
End Page
23317
DOI
10.1074/jbc.M112.344762

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, C. T., et al. “LKLF: A transcriptional regulator of single-positive T cell quiescence and survival.Science, vol. 277, no. 5334, Sept. 1997, pp. 1986–90. Pubmed, doi:10.1126/science.277.5334.1986.
URI
https://scholars.duke.edu/individual/pub782383
PMID
9302292
Source
pubmed
Published In
Science (New York, N.Y.)
Volume
277
Published Date
Start Page
1986
End Page
1990
DOI
10.1126/science.277.5334.1986

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.
Authors
Pan, Y-W; Chan, GCK; Kuo, CT; Storm, DR; Xia, Z
MLA Citation
URI
https://scholars.duke.edu/individual/pub782377
PMID
22573667
Source
pubmed
Published In
Journal of Neuroscience
Volume
32
Published Date
Start Page
6444
End Page
6455
DOI
10.1523/JNEUROSCI.6076-11.2012

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-/-) mice died between 8.5 and 10.5 days post coitum (dpc). GATA4-/- 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-/- 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-/- 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-/- procardiomyocytes was not cell intrinsic because GATA4-/- cardiac myocytes and endocardial cells populated the hearts of GATA4-/- -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, C. T., et al. “GATA4 transcription factor is required for ventral morphogenesis and heart tube formation.Genes Dev, vol. 11, no. 8, Apr. 1997, pp. 1048–60. Pubmed, doi:10.1101/gad.11.8.1048.
URI
https://scholars.duke.edu/individual/pub782385
PMID
9136932
Source
pubmed
Published In
Genes & Development
Volume
11
Published Date
Start Page
1048
End Page
1060
DOI
10.1101/gad.11.8.1048