Chay T. Kuo, BS (MIT), MD/PhD (University of Chicago)
George W. Brumley Associate 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
Regenerative capacities in the adult nervous system
We are interested in understanding regenerative capacities in the nervous system, using rodent neurogenesis and fly metamorphosis as model systems. A major part of our current efforts is focused on how to sustain neurogenesis in the adult brain. The answers to this question may be similar to: when do we decide it is time to buy a new computer? Often it is when the hardware can no longer keep up with sophisticated software. Since we are taught that we can’t upgrade our brains (the hardware), how does it keep up as we fill it with new experiences/tasks/skills? Is this accomplished purely by strengthening/weakening/remodeling of existing connections between cells, or could we complement these processes by making and integrating new useful neurons?
We are studying the assembly and function of a neural stem cell niche in the adult rodent brain leading to this possibility. In addition to molecular analyses of lateral ventricular (LV) niche homeostasis under physiological and injury conditions, through a chemical screen we found that cholinergic modulators have robust effects on adult LV neurogenesis ex vivo. In search of potential sources for acetylcholine (ACh) in the LV niche, we uncovered direct cholinergic innervation from previously undescribed subependymal ChAT+ (subep-ChAT+) neurons. These novel cholinergic neurons display morphological and functional differences from neighboring striatal counterparts, and releases ACh into the LV niche in activity-dependent fashion. Our genetic, optogenetic, and electrophysiology experiments showed that subep-ChAT+ neuron activity can directly control adult LV neurogenic proliferation.
Contrary to the view that adult LV neurogenesis is primarily directed by stem-cell intrinsic and local signals, including neurotransmitters acting through bulk-release mechanisms, we have discovered an undescribed gateway connecting neural network activity states to LV NSC proliferation. We are interested in what lies beyond this gateway, and there are many questions to answer going forward, with potentials for modulating neuroregenerative capacities in health and after injury.
Niche control of new neuron production in the adult brain
Early on, we developed some of the first tamoxifen-inducible genetic tools to study adult rodent LV 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 developed assays to uncover that cellular properties within multiciliated ependymal cells, part of the neurogenic niche, provide critical cues. And we have discovered novel mature neurons as part of the local niche, connecting LV neurogenesis to circuit-level instructions. We are integrating cellular and neuronal network-level analyses to formulate general principles guiding new neuron production in the adult brain. We use a variety of techniques including generation of new imaging tools, slice electrophysiological, and collaborations with bioengineers to study these processes.
Contribution of NSCs and their progeny to brain repair and remodeling after injury
Our strategies to disrupt the rodent LV neurogenic niche revealed that resident NSCs have considerable plasticity, and can participate in local remodeling and cortical injury repair. We are investigating the underlying mechanisms regulating this plasticity. We are interested in how systemic cues can influence the differentiation of 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. We discovered that cortical injury induces LV niche switching from neurogenesis to robust astrogenesis, producing distinct Thbs4hi astrocytes migrating to the injury site. This astrogenesis response is critical for proper glial scar formation to stop cortical bleeding after injury. Our ability to modify adult NSC progeny fates, under physiological and injury conditions, gives us unique opportunities to tackle brain injury repair, a challenging and medically important problem. Our approaches include a combination of mouse genetics, molecular analyses, live-cell imaging, electrophysiology and optogenetics, and collaborations with neural trauma colleagues.
Paez-Gonzalez, P, Asrican, B, Rodriguez, E, and Kuo, CT. (2014) Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis. Nat. Neurosci., doi: 10.1038/nn.3734.
Lyons, GR, Andersen, RO, Abdi, K, Song WS, Kuo, CT (2014) Cysteine Proteinase-1 and Cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron. Cell Reports 6:783-91. (Cover story)
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 (Research highlights in Nature Rv. Neurosci.)
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 (News & Views in Nature Immunol.)
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 (Cover story)
Kuo CT, Veselits ML, Leiden JM (1997) LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science 277(5334):1986-90 (Perspectives in Science)