Molecular Mechanisms of Sensory Neurogenesis

Summary

Principal Investigator: Eric Huang
Abstract: The sensory nervous system is a common target for genetic diseases, metabolic disorders, and traumatic injuries. It has recently been shown that a cascade of transcription factors controls development of vertebrate sensory nervous system. Among these, POU domain factor Brn-3a regulates expression of genes that are important for sensory neuron survival, phenotypic differentiation, and axon path finding. Although Brn-3a is present in almost all precursors in the sensory ganglia, loss of Brn-3a leads to specific down-regulation of neurotrophin receptors and cell death in sensory neurons, suggesting that additional factors may modulate Brn-3a functions during sensory neuron development. Using the yeast two-hybrid screen, we have identified a novel nuclear kinase, homeodomain protein kinase 2 (HIPK2) that interacts with the POU homeodomain of Brn-3a, enhances Brn-3a-DNA interactions, and modulates Bm-3a-mediated gene expression. Based on these data, we hypothesize that HIPK2 is a transcription cofactor that regulates Brn-3a functions at different stages of sensory neuron development. However, because of its ability to interact with other homeodomain proteins, HIPK2 may also regulate neuronal functions via Bm-3a-independent pathways. The main objective of the proposed study is to investigate the mechanisms by which HIPK2 regulates sensory neuron functions. We propose the following specific aims to achieve this goal. Aim 1: To characterize the-nature of Bm-3a-HIPK2 interaction and to demonstrate such interactions during different stages of sensory neurogenesis. Aim 2: To determine if HIPK2 can modulate Brn-3a functions by phosphorylation. Aim 3: To characterize the roles of HIPK2 in regulating gene expression, survival, and axon path finding in sensory and sympathetic neurons. Aim 4: To investigate the mechanisms that regulates the distribution of HIPK2 during sensory neuron differentiation. Understanding the molecular mechanisms that regulate Brn-3a and HIPK2 functions will lead to important insights regarding the control of survival, differentiation and axon path finding of sensory neurons during development, injury, and regeneration. The interdisciplinary nature of this research program necessitates the central involvement of the PI in training students and postdoctoral fellows in the research areas in which they are inexperienced. The funding of this proposal would enable the PI to devote much of his efforts to research and significantly enhance the ability of the PI to accomplish his goals in research by reducing his clinical, teaching and administrative duties.
Funding Period: 2002-09-30 - 2007-08-31
more information: NIH RePORT

Top Publications

  1. pmc Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization
    Eric J Huang
    Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA
    Genes Dev 19:138-51. 2005
  2. ncbi Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice
    Stephen Lynn
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
    Free Radic Biol Med 38:817-28. 2005
  3. pmc Dynamic expression of neurotrophic factor receptors in postnatal spinal motoneurons and in mouse model of ALS
    Jiasheng Zhang
    Department of Pathology, University of California San Francisco and Pathology, Service 113B, VA Medical Center, 94121, USA
    J Neurobiol 66:882-95. 2006
  4. pmc Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons
    Jiasheng Zhang
    Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA
    Nat Neurosci 10:77-86. 2007
  5. pmc Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice
    R R Laposa
    Department of Dermatology and Cancer Center, University of California, San Francisco, CA 94143 0808, USA
    Proc Natl Acad Sci U S A 104:1389-94. 2007
  6. pmc HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis
    Guangwei Wei
    Department of Pathology, University of California and Pathology Service 113B, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    Proc Natl Acad Sci U S A 104:13040-5. 2007
  7. pmc Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons
    Mianzhi Tang
    VA Medical Center and Department of Pathology, University of California San Francisco, San Francisco, CA 94121, USA
    Development 136:2027-38. 2009

Scientific Experts

  • E J Huang
  • Jiasheng Zhang
  • Mianzhi Tang
  • Guangwei Wei
  • R R Laposa
  • Stephen Lynn
  • Yasunori Miyamoto
  • J E Cleaver
  • Amy T Tang
  • Jian Hua Mao
  • Shin ichi Saito
  • Joanna Hellmuth
  • Ettore Appella
  • Allan Balmain
  • Patricia H Janak
  • Siuwah Tang
  • Laurence H Tecott
  • Gene K Ma
  • Vanee Pho
  • Stephen J Bonasera
  • Jed Holtzman
  • Amy A Tang
  • Stephen Ku
  • Yumiko Nishinaka
  • Sailaja Elchuri
  • Charles J Epstein
  • Mohammed Naeemuddin
  • Junji Yodoi
  • Donna M Ferriero
  • Ting Ting Huang

Detail Information

Publications7

  1. pmc Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization
    Eric J Huang
    Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA
    Genes Dev 19:138-51. 2005
    ..Taken together, our data provide evidence for previously unidentified functions of Numb and Numblike in sensory axon arborization by regulating Notch1 via the endocytic-lysosomal pathways...
  2. ncbi Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice
    Stephen Lynn
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
    Free Radic Biol Med 38:817-28. 2005
    ..Other major classes of differentially expressed genes include lipid biosynthesis and ROS metabolism...
  3. pmc Dynamic expression of neurotrophic factor receptors in postnatal spinal motoneurons and in mouse model of ALS
    Jiasheng Zhang
    Department of Pathology, University of California San Francisco and Pathology, Service 113B, VA Medical Center, 94121, USA
    J Neurobiol 66:882-95. 2006
    ..These results provide insights into the use of neurotrophic factors as therapeutic agents for ALS...
  4. pmc Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons
    Jiasheng Zhang
    Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA
    Nat Neurosci 10:77-86. 2007
    ..These data underscore the importance of the TGFbeta-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration...
  5. pmc Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice
    R R Laposa
    Department of Dermatology and Cancer Center, University of California, San Francisco, CA 94143 0808, USA
    Proc Natl Acad Sci U S A 104:1389-94. 2007
    ....
  6. pmc HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis
    Guangwei Wei
    Department of Pathology, University of California and Pathology Service 113B, Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    Proc Natl Acad Sci U S A 104:13040-5. 2007
    ..Together, our results indicate that HIPK2 is a tumor suppressor that controls proliferation by antagonizing LEF1/beta-catenin-mediated transcription. Loss of HIPK2 synergizes with activation of H-ras to induce tumorigenesis...
  7. pmc Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons
    Mianzhi Tang
    VA Medical Center and Department of Pathology, University of California San Francisco, San Francisco, CA 94121, USA
    Development 136:2027-38. 2009
    ..They also suggest that beta-catenin-mediated signaling pathways can be targeted to promote and expand DA neurons in cell-based therapeutic strategies...