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

Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and after Injury.

Lineage development is a stepwise process, governed by stage-specific regulatory factors and associated markers. Astrocytes are one of the principle cell types in the CNS and the stages associated with their development remain very poorly defined. To identify these stages, we performed gene-expression profiling on astrocyte precursor populations in the spinal cord, identifying distinct patterns of gene induction during their development that are strongly correlated with human astrocytes. Validation studies identified a new cohort of astrocyte-associated genes during development and demonstrated their expression in reactive astrocytes in human white matter injury (WMI). Functional studies on one of these genes revealed that mice lacking Asef exhibited impaired astrocyte differentiation during development and repair after WMI, coupled with compromised blood-brain barrier integrity in the adult CNS. These studies have identified distinct stages of astrocyte lineage development associated with human WMI and, together with our functional analysis of Asef, highlight the parallels between astrocyte development and their reactive counterparts associated with injury. SIGNIFICANCE STATEMENT: Astrocytes play a central role in CNS function and associated diseases. Yet the mechanisms that control their development remain poorly defined. Using the developing mouse spinal cord as a model system, we identify molecular changes that occur in developing astrocytes. These molecular signatures are strongly correlated with human astrocyte expression profiles and validation in mouse spinal cord identifies a host of new genes associated with the astrocyte lineage. These genes are present in reactive astrocytes in human white matter injury, and functional studies reveal that one of these genes, Asef, contributes to reactive astrocyte responses after injury. These studies identify distinct stages of astrocyte lineage development and highlight the parallels between astrocyte development and their reactive counterparts associated with injury.
Authors
Chaboub, LS; Manalo, JM; Lee, HK; Glasgow, SM; Chen, F; Kawasaki, Y; Akiyama, T; Kuo, CT; Creighton, CJ; Mohila, CA; Deneen, B
MLA Citation
Chaboub, Lesley S., et al. “Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and after Injury.J Neurosci, vol. 36, no. 47, Nov. 2016, pp. 11904–17. Pubmed, doi:10.1523/JNEUROSCI.1658-16.2016.
URI
https://scholars.duke.edu/individual/pub1159238
PMID
27881777
Source
pubmed
Published In
Journal of Neuroscience
Volume
36
Published Date
Start Page
11904
End Page
11917
DOI
10.1523/JNEUROSCI.1658-16.2016

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, Chay T., et al. “Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning.Neuron, vol. 51, no. 3, Aug. 2006, pp. 283–90. Pubmed, doi:10.1016/j.neuron.2006.07.014.
URI
https://scholars.duke.edu/individual/pub698909
PMID
16880123
Source
pubmed
Published In
Neuron
Volume
51
Published Date
Start Page
283
End Page
290
DOI
10.1016/j.neuron.2006.07.014

Low excitatory innervation balances high intrinsic excitability of immature dentate neurons.

Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.
Authors
Dieni, CV; Panichi, R; Aimone, JB; Kuo, CT; Wadiche, JI; Overstreet-Wadiche, L
MLA Citation
Dieni, Cristina V., et al. “Low excitatory innervation balances high intrinsic excitability of immature dentate neurons.Nat Commun, vol. 7, Apr. 2016, p. 11313. Pubmed, doi:10.1038/ncomms11313.
URI
https://scholars.duke.edu/individual/pub1129651
PMID
27095423
Source
pubmed
Published In
Nature Communications
Volume
7
Published Date
Start Page
11313
DOI
10.1038/ncomms11313

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, Fengwei, et al. “Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology.Neuron, vol. 51, no. 1, July 2006, pp. 13–20. Pubmed, doi:10.1016/j.neuron.2006.06.016.
URI
https://scholars.duke.edu/individual/pub698906
PMID
16815328
Source
pubmed
Published In
Neuron
Volume
51
Published Date
Start Page
13
End Page
20
DOI
10.1016/j.neuron.2006.06.016