The control of neural development and maintenance of neuronal differentiation requires a delicate balance of gene expression. Research in my lab investigates the signaling mechanisms and transcriptional programs that regulate the developing mouse nervous system. There are three main areas of focus.
1. Transcriptional Control of Neuronal Survival
One major focus uses the sensory nervous system as a model to explore the molecular mechanisms that orchestrate proliferation of progenitors, differentiation of distinct neuronal lineages, and maintenance of survival. We have shown that the interaction between transcription factor Brn3a and corepressor HIPK2 regulates a delicate balance of gene expression during programmed cell death in sensory ganglia (published in JCB and Curr Biol ). Loss of Brn3a results in reductions in the expression of Bcl-x L and TrkA, and a severe loss of sensory neurons. Conversely, targeted deletion of HIPK2 leads to increases in Brn3a downstream targets and a significant reduction in programmed cell death. Interestingly, the function of HIPK2 is not limited to the sensory nervous system as HIPK2 mutants show prominent Parkinsonian features with selective loss of dopaminergic neurons in the substantia nigra. Our immediate goal is to determine the upstream signaling mechanisms by which HIPK2 regulates the development of these dopaminergic neurons.
2. Transcriptional Programs and Tumor Suppression
Emerging data also indicate that loss of HIPK2 leads to a marked increase in cell proliferation in mouse embryonic fibroblasts and that HIPK2 mutants show an increased propensity for tumorigenesis. While the detailed mechanism awaits further work, our preliminary data indicate that HIPK2 is an essential component in the non-canonical Wnt signaling pathway, which suppresses the b -catenin-mediated regulation of cyclin D1 expression. Our immediate goal is to further delineate mechanism of HIPK2 functions and the signaling pathways that regulate HIPK2. Our ultimate goal is to identify a unified model for HIPK2 that can be applied to both neural development and in tumorigenesis.
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. 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. 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 activate Notch cleavage in neurodegenerative diseases. |
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.
information last updated January 2005 |
Biomedical Sciences (BMS) Graduate Program
