Chay T. Kuo, BS (MIT), MD/PhD (University of Chicago)
George W. Brumley Assistant Professor,
Dept. of Cell Biology, Pediatrics, Neurobiology
366 Nanaline Duke Bldg.
451 Research Dr.
Duke Univ. Medical Center
Durham, NC 27710
Telephone: (919) 684-4612 Fax: (919) 684-5481
Adult neurogenesis and regenerative capacities in the nervous system
We are interested in the regulation of postnatal/adult neural stem cells (NSCs) and how they modify brain homeostasis in health and disease. Throughout embryonic and postnatal development, NSCs 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 NSCs, 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 NSC proliferation/differentiation into glia. A better understanding of these processes may lead to future therapies for patients suffering from pre/postnatal brain injuries.
Control of neurogenic niche homeostasis and neuronal production
For most of our experiments, we use the rodent postnatal/adult subventricular zone (SVZ) neurogenic niche as a model system. This is an adult brain area that contains robust self-renewing NSC populations. Early on, we developed some of the first tamoxifen-inducible genetic tools to modulate SVZ niche function in vivo, and have continued to work in this area by merging mouse genetics with optical and physiology tools. As it was unclear how new neuron production was sustained in the postnatal/adult brain, we uncovered that cellular properties within multiciliated ependymal cells, part of the neurogenic niche, provide critical cues to sustain neurogenesis in the postnatal/adult brain. A focus in the lab is to elucidate molecular pathways regulating adult NSC homeostasis within the functional niche - we are particularly interested in how this niche architecture is generated and maintained, and in the application of this knowledge to formulate general principles guiding new neuron production in the adult brain. We use a variety of techniques including generation of new genetic tools, development of live-imaging platforms, whole-cell electrophysiological recordings, and collaborations with bioengineers to study these processes. We are conducting both in vivo and in vitro-based screens to identify pathways that can sustain postnatal/adult neurogenesis.
Contribution of NSCs and their progeny to brain repair and remodeling after injury
Our genetic strategies to postnatally disrupt the SVZ neurogenic niche revealed that resident NSCs have considerable plasticity, and can participate in local remodeling and tissue repair. We are investigating the cellular mechanisms underlying this plasticity. We are interested in how environmental cues may influence the differentiation of postnatal/adult NSCs into either neurons or astrocytes, and how this process can functionally impact brain homeostasis in both health (integration of newborn neurons into mature neural circuits) and after brain injury (migration of unique astrocytes following cortical stroke). Our ability to label and modify adult NSC progeny, under different environmental conditions, gives us unique opportunities to tackle these challenging and medically important problems. We believe that a deeper understanding of resident NSC’s innate responses to pathological conditions should accelerate future therapeutic development for patients. Our approaches include a combination of mouse genetics, in vitro stem cell assays, live-cell imaging, electrophysiology, and collaboration with neural trauma colleagues.
Benner, EJ, Luciano, D, Jo, R, Abdi, K, Paez-Gonzalez, P, Sheng, H, Warner, DS, Liu, C, Eroglu, C, and Kuo, CT. (2013) Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497: 369-73.
Paez-Gonzalez, P, Abdi, K., Luciano, D, Liu, Y, Soriano-Navarro, M, Rawlins, E, Bennett, V, Garcia-Verdugo, JM, and Kuo, CT. (2011) Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron 71: 61-75. (Cover Story)
Kuo, CT, Mirzadeh, Z, Soriano, M, Rasin, M, Wang, D, Shen, J, Sestan, N, Garcia-Verdugo, J, Alvarez-Buylla, A, Jan, LY, and Jan, YN. (2006) Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche. Cell 127: 1253-64. (Research Highlights in Nature)
Kuo CT, Zhu S, Younger S, Jan LY, Jan YN (2006) Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron. 51(3):283-90
Yu F, Kuo CT, Jan YN (2006) Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology. Neuron. 51(1):13-20
Kuo CT, Jan LY, Jan YN (2005) Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling. Proc Natl Acad Sci USA. 102(42):15230-5
Buckley AF, Kuo CT, Leiden JM (2001) Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway. Nature Immunol. 2(8): 698-704
Kuo CT and Leiden JM (1999) Transcriptional Regulation of T Lymphocyte Development and Function. Annu Rev Immunol. 17:149-87
Kuo CT, Veselits ML, Barton KP, Lu MM, Clendenin C, and Leiden JM (1997) The LKLF transcription factor is required for normal tunica media formation and blood stabilization during murine embryogenesis. Genes and Dev. 11(22):2996-3006
Kuo CT, Veselits ML, Leiden JM (1997) LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science 277(5334):1986-90