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:

Multidisciplinary Neonatal Training Grant

Administered By
Pediatrics, Neonatology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Basic predoctoral training in neuroscience

Administered By
Neurobiology
Awarded By
National Institutes of Health
Role
Training Faculty
Start Date
End Date

Training in Fundamental &Translational Neuroscience

Administered By
Neurobiology
Awarded By
National Institutes of Health
Role
Training Faculty
Start Date
End Date

Serial Block Face Scanning Electron Microscope

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Major User
Start Date
End Date

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

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

Discerning Neurogenic vs. Non-Neurogenic Postnatal Lateral Ventricular Astrocytes via Activity-Dependent Input.

Throughout development, neural stem cells (NSCs) give rise to differentiated neurons, astrocytes, and oligodendrocytes which together modulate perception, memory, and behavior in the adult nervous system. To understand how NSCs contribute to postnatal/adult brain remodeling and repair after injury, the lateral ventricular (LV) neurogenic niche in the rodent postnatal brain serves as an excellent model system. It is a specialized area containing self-renewing GFAP(+) astrocytes functioning as NSCs generating new neurons throughout life. In addition to this now well-studied regenerative process, the LV niche also generates differentiated astrocytes, playing an important role for glial scar formation after cortical injury. While LV NSCs can be clearly distinguished from their neuroblast and oligodendrocyte progeny via molecular markers, the astrocytic identity of NSCs has complicated their distinction from terminally-differentiated astrocytes in the niche. Our current models of postnatal/adult LV neurogenesis do not take into account local astrogenesis, or the possibility that cellular markers may be similar between non-dividing GFAP(+) NSCs and their differentiated astrocyte daughters. Postnatal LV neurogenesis is regulated by NSC-intrinsic mechanisms interacting with extracellular/niche-driven cues. It is generally believed that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have suggested possibilities for neural circuit-level modulation. With recent experimental findings that neuronal stimulation can directly evoke responses in LV NSCs, it is possible that this exciting property will add a new dimension to identifying postnatal/adult NSCs. Here, we put forth a notion that neural circuit-level input can be a distinct characteristic defining postnatal/adult NSCs from non-neurogenic astroglia.
Authors
Adlaf, EW; Mitchell-Dick, A; Kuo, CT
MLA Citation
Adlaf, Elena W., et al. “Discerning Neurogenic vs. Non-Neurogenic Postnatal Lateral Ventricular Astrocytes via Activity-Dependent Input.Front Neurosci, vol. 10, 2016, p. 111. Pubmed, doi:10.3389/fnins.2016.00111.
URI
https://scholars.duke.edu/individual/pub1127622
PMID
27047330
Source
pubmed
Published In
Frontiers in Neuroscience
Volume
10
Published Date
Start Page
111
DOI
10.3389/fnins.2016.00111

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, Chay T., et al. “Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling.Proc Natl Acad Sci U S A, vol. 102, no. 42, Oct. 2005, pp. 15230–35. Pubmed, doi:10.1073/pnas.0507393102.
URI
https://scholars.duke.edu/individual/pub698908
PMID
16210248
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
102
Published Date
Start Page
15230
End Page
15235
DOI
10.1073/pnas.0507393102

Cholinergic Circuit Control of Postnatal Neurogenesis.

New neuron addition via continued neurogenesis in the postnatal/adult mammalian brain presents a distinct form of nervous system plasticity. During embryonic development, precise temporal and spatial patterns of neurogenesis are necessary to create the nervous system architecture. Similar between embryonic and postnatal stages, neurogenic proliferation is regulated by neural stem cell (NSC)-intrinsic mechanisms layered upon cues from their local microenvironmental niche. Following developmental assembly, it remains relatively unclear what may be the key driving forces that sustain continued production of neurons in the postnatal/adult brain. Recent experimental evidence suggests that patterned activity from specific neural circuits can also directly govern postnatal/adult neurogenesis. Here, we review experimental findings that revealed cholinergic modulation, and how patterns of neuronal activity and acetylcholine release may differentially or synergistically activate downstream signaling in NSCs. Higher-order excitatory and inhibitory inputs regulating cholinergic neuron firing, and their implications in neurogenesis control are also considered.
Authors
Asrican, B; Paez-Gonzalez, P; Erb, J; Kuo, CT
MLA Citation
Asrican, Brent, et al. “Cholinergic Circuit Control of Postnatal Neurogenesis.Neurogenesis (Austin), vol. 3, no. 1, 2016. Pubmed, doi:10.1080/23262133.2015.1127310.
URI
https://scholars.duke.edu/individual/pub1139044
PMID
27468423
Source
pubmed
Published In
Neurogenesis (Austin, Tex.)
Volume
3
Published Date
DOI
10.1080/23262133.2015.1127310

The hand that rocks the spindle.

Authors
Kuo, CT; Jan, Y-N
MLA Citation
Kuo, Chay T., and Yuh-Nung Jan. “The hand that rocks the spindle.Nat Cell Biol, vol. 7, no. 9, Sept. 2005, pp. 858–59. Pubmed, doi:10.1038/ncb0905-858.
URI
https://scholars.duke.edu/individual/pub698907
PMID
16136185
Source
pubmed
Published In
Nature Cell Biology
Volume
7
Published Date
Start Page
858
End Page
859
DOI
10.1038/ncb0905-858