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Neuroscience Graduate Program at UCSF
Transcriptional Programs in Neuronal Survival and Differentiation
The control of neural development and the maintenance of neuronal differentiation and survival require a delicate balance of gene expression. Research in my lab investigates the signaling mechanisms and transcriptional programs that regulate the developing mouse nervous system. Our ultimate goal is to provide an integrated view on how trophic factors influence neuron functions through regulation of gene expression.
1. Transcriptional Control of Neuronal Survival
The sensory nervous system is an elegant model system to explore the molecular mechanisms that orchestrate proliferation of progenitors, cell fate determination, subtype specification, and maintenance of survival. A major effort in my lab has been to study the transcriptional mechanisms that regulate survival and programmed cell death in sensory neurons during development. Our earlier efforts have identified POU domain transcription factor as an important molecule in maintaining the expression of neurotrophin receptors and Bcl-x L. Loss of Brn3a leads to expansion of programmed cell death and a precipitous loss of sensory neurons. More recently, we have shown that the control of Brn3a-mediated gene expression depends upon interactions between transcription factor Brn3a and corepressor HIPK2. Such interactions regulate a delicate balance of gene expression during programmed cell death in sensory ganglia. In contrast to the loss of Brn3a phenotype, targeted deletion of HIPK2 leads to increases in Brn3a downstream targets and a significant reduction in programmed cell death. Future directions include investigations of how neurotrophins regulate the nucleus-to-cytoplasm translocation of HIPK2 and its roles in the more general scheme of neurotrophin-mediated neuronal survival.
2. Trophic Factor Dependence and Transcriptional Mechanisms
Recent literature has indicated that transcriptional cofactors may also serve important functions at the interface of trophic factor-dependent signaling pathways and regulation of gene expression. Indeed, several lines of evidence show that HIPK2 can be detected in multimeric protein complexes in the downstream of TGFbeta and Wnt. However, the mechanisms and its biological implications are entirely unclear. Our preliminary results indicate that, in contrast to the sensory ganglia, expression of Brn3a and HIPK2 is present in distinctly different domain in the ventral midbrain during development and in adulthood. Unlike the sensory nervous system, loss of HIPK2 leads to a selective loss of midbrain dopaminergic neurons in substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). As a consequence, HIPK2 mutants show prominent Parkinsonian features and motor behavioral phenotype consistent with the cellular deficits. Our immediate goal is to determine the upstream signaling mechanisms by which HIPK2 regulates the development of these dopaminergic neurons.
3. Notch Activation, Neural Development and Neurodegeneration
Another focus of the lab investigates the role of Notch activation in the development of sensory neurons and in neurodegeneration. Using conditional knockout approach, we showed that removal of Notch antagonists Numb and Numblike (Nbl) had no effect on neurogenesis in the sensory ganglia (in collaboration with Dr. YN Jan). Instead, loss of Numb and Nbl resulted in a significant increase in the activated Notch (Notch intracellular domain or NICD) in the nuclei. As a consequence, sensory neurons showed severe deficits in axonal arborization. While the exact mechanism is still unclear, evidence indicated that Numb, and to a lesser extent Nbl, may regulate endocytosis and recycling of Notch. Activation of Notch not only regulate axonal arborization in the developing sensory neurons, it also plays important role in neurodegeneration (in collaboration with Dr. DeArmond). For instance, cortical neurons expressing scrapie form of prion proteins (PrP SC) showed significant accumulation of NICD, which correlated tightly with the disease progression. Reducing Notch by siRNA reversed similar abnormalities in PrP SC-infected N2A cells. Our future direction is to study the role of NICD as a transcriptional repressor for neuronal genes and to determine the mechanism that activates Notch cleavage in neurodegenerative diseases.
(Research in the Huang lab is supported by the NIH, VA, NPF, MJFF and PECASE.)
Ku, Stephen
UCSF Medical Student
B.S., Stanford University
Pho, Vanee
Postdoctoral Fellow
Ph.D., Boston University
Tang, Amy
Staff Research Associate
B.S., UC Berkeley
Tang, Mike
Lab Technician
B.S., UC Berkeley
Wei, Guangwei
Postdoctoral Fellow
Ph.D., Fudan University
Wiggins, Amanda
Postdoctoral Fellow
Ph.D., University of Melbourne
Zhang, Jiasheng
Postdoctoral Fellow
Ph.D., Kanazawa University
Huang, E.J. and Reichardt, L.F. Neurotrophins: Roles in Neuronal Development and Function. Ann Rev Neurosci 24:677-736, 2001.
Huang, E.J. and Reichardt, L.F. Trk receptors: Roles in Neuronal Signal Transduction. Ann Rev Biochem 72:609-642, 2003.
Chen, T.T., Brown, E.J., Huang, E.J.and Seaman, W.E. Expression and activation of signal regulatory protein alpha on astrocytomas. Cancer Res. 64(1):117-27, 2004.
Wiggins, A.K., Wei, G., Doxakis, E., Wong, C., Tang, A.A., Zeng, K., Luo, E.J., Neve, R.L., Reichardt, L.F. and Huang, E.J. Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival. J Cell Biol 167 (2): 257-267, 2004.
Doxakis, E., Huang, E.J. and Davies, A.M. Homeodomain interacting protein kinase 2 (HIPK2) regulates apoptosis in developing sensory and sympathetic neurons. Curr Biol 14(19): 1761-1765, 2004.
Huang, E.J., Li, H., Tang, A.A., Wiggins, A.K., Neve, R.L., Zhong, W., Jan, L.Y. and Jan, Y.N. Targeted deletion of Numb and Numblike reveals their essential functions in axon arborization. Genes & Dev 19(1): 138-151, 2005.
Ishikura, N., Clever, J.L., Bouzamondo Berstein, E., Prusiner, S.B., Huang, E.J. and DeArmond, E.J. Notch-1 activation and dendritic atrophy in prion disease. Proc Natl Acad Sci ( USA) 102(3): 886-889, 2005.
Lynn, S., Huang, E.J., Elchuri, S., Naeemuddin, M., Nishinaka, Y., Yodoi, J., Ferriero, D.M., Epstein, C.J. and Huang, T.T. Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice. Free Rad Biol Med 38(6):817-828, 2005.
Eric J. Huang, M.D./Ph.D.
Phone
415-221-4810 x2620
Physical Address
VA Medical Center,
Bldg 2, Rm 355B
4150 Clement Street
San Francisco, CA 94121
Mailing Address
Pathology Service 113B VAMC
4150 Clement Street
San Francisco, CA 94121
Other Websites
Lab website (under construction)
PIBS Website (coming soon)