MECHANISMS OF NEURAL PATTERNING IN MAMMALIAN FOREBRAIN

Summary

Principal Investigator: Gordon Fishell
Abstract: This grant examines the role of Notch signaling in cerebellar cell specification. Here we investigate how Notch signaling contributes to the emergence of discrete cerebellar proliferative zones which in turn generate specific subsets of cerebellar cells. In this regard, we present a hypothesis of how Notch signaling acts in this process and investigate how antagonism between Notch and Math1 signaling contribute to the establishment and maintenance of the rhombic lip versus the main cerebellar ventricular zone. Central to this model is an examination of how Notch and BMP signaling interact in modulating Math1 expression during early cerebellar development. Work from genetic and gain-of-function analysis suggests that BMP signaling directs cerebellar progenitors to express Math1 and join the rhombic lip. We suggest that Notch signaling modulates this process by making cerebellar cells deaf to BMP inductive signals, thus maintaining progenitors in the main cerebellar ventricular zone. It is notable in this regard that constitutive Notch signaling results in progenitors becoming Bergmann radial glia. Based on both our own previous work in the forebrain, and work by others, radial glia may represent a stem cell population. Our preliminary work suggests that the same is true in the cerebellum. In this regard, we have shown that pluripotent progenitors exist in the cerebellum throughout embryonic development and that they express the radial glial marker BLBP. We will apply in vitro and in vivo methods to see if like in the forebrain Notch activation bestows stem cell potential on cerebellar cells. To complement this approach we will look at whether endogenous cerebellar radial glia possess stem cell properties, by doing a parallel examination of cerebellar radial glia isolated by their expression of GFP whose expression is directed by a BLBP promoter. To extend these studies, we also propose to fate map endogenous cerebellar radial glial using a genetic approach. In the long term our goal is to investigate whether the cerebellum has the capacity to undergo regeneration and whether we can use transplantation to augment neural repair in the cerebellum and more broadly the CNS in general.
Funding Period: 1995-04-07 - 2008-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors
    Rob Machold
    Department of Cell Biology, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, 540 First Avenue, New York, New York 10016, USA
    Neuron 48:17-24. 2005
  2. pmc Mechanisms of inhibition within the telencephalon: "where the wild things are"
    Gord Fishell
    Smilow Neuroscience Program, Smilow Research Center, New York University School of Medicine, New York, New York 10016, USA
    Annu Rev Neurosci 34:535-67. 2011
  3. pmc Sonic hedgehog functions through dynamic changes in temporal competence in the developing forebrain
    Vitor H Sousa
    Smilow Neuroscience Program, Department of Cell Biology, New York University Langone Medical Center, New York, NY 10016, USA
    Curr Opin Genet Dev 20:391-9. 2010
  4. ncbi Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system
    Rosalind S E Carney
    Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA
    J Neurosci 26:11562-74. 2006
  5. pmc Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip
    Robert P Machold
    New York University School of Medicine, Smilow Neuroscience Program, Department of Cell Biology, 522 First Avenue, New York, NY 10016, USA
    Neural Dev 2:5. 2007
  6. ncbi The role of Foxg1 and dorsal midline signaling in the generation of Cajal-Retzius subtypes
    Carina Hanashima
    Smilow Neuroscience Program and Department of Cell Biology, Smilow Research Center, New York University, New York, New York 10016, USA
    J Neurosci 27:11103-11. 2007
  7. ncbi Perspectives on the developmental origins of cortical interneuron diversity
    Gordon Fishell
    Smilow Neuroscience Program, Department of Cell Biology, Floor Smilow Research Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA
    Novartis Found Symp 288:21-35; discussion 35-44, 96-8. 2007
  8. pmc The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes
    Simon J B Butt
    Smilow Neuroscience Program and the Department of Cell Biology, New York University, New York, NY 10016, USA
    Neuron 59:722-32. 2008

Scientific Experts

  • Robert P Machold
  • Gord Fishell
  • Vitor H Sousa
  • Simon J B Butt
  • Gordon Fishell
  • Carina Hanashima
  • Rosalind S E Carney
  • Bernardo Rudy
  • Jens Hjerling-Leffler
  • Goichi Miyoshi
  • Shioko Kimura
  • Marc V Fuccillo
  • Marie Fernandes
  • Jean M Hebert
  • Barbara S Bregman
  • Haining Dai
  • Jonathan Slotkin
  • Bogdan Stoica
  • Daniela Cohen
  • Joshua G Corbin
  • Susana Nery
  • Teresa B Alfonso

Detail Information

Publications8

  1. ncbi Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors
    Rob Machold
    Department of Cell Biology, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, 540 First Avenue, New York, New York 10016, USA
    Neuron 48:17-24. 2005
    ..Thus, we demonstrate that the cerebellar rhombic lip gives rise to multiple cell types within rhombomere 1...
  2. pmc Mechanisms of inhibition within the telencephalon: "where the wild things are"
    Gord Fishell
    Smilow Neuroscience Program, Smilow Research Center, New York University School of Medicine, New York, New York 10016, USA
    Annu Rev Neurosci 34:535-67. 2011
    ..Finally we speculate regarding the attractiveness and challenges of establishing a unifying nomenclature to describe inhibitory neuron diversity throughout the telencephalon...
  3. pmc Sonic hedgehog functions through dynamic changes in temporal competence in the developing forebrain
    Vitor H Sousa
    Smilow Neuroscience Program, Department of Cell Biology, New York University Langone Medical Center, New York, NY 10016, USA
    Curr Opin Genet Dev 20:391-9. 2010
    ..We suggest these developmental changes in competence are mediated by a transcriptional mechanism that intrinsically integrates information from the distinct signaling pathways that act to pattern the telencephalic neuroepithelium...
  4. ncbi Cell migration along the lateral cortical stream to the developing basal telencephalic limbic system
    Rosalind S E Carney
    Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA
    J Neurosci 26:11562-74. 2006
    ..We further demonstrate that the generation of the LCS is dependent on the homeodomain-containing gene Gsh2, revealing a novel requirement for Gsh2 in telencephalic development...
  5. pmc Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip
    Robert P Machold
    New York University School of Medicine, Smilow Neuroscience Program, Department of Cell Biology, 522 First Avenue, New York, NY 10016, USA
    Neural Dev 2:5. 2007
    ....
  6. ncbi The role of Foxg1 and dorsal midline signaling in the generation of Cajal-Retzius subtypes
    Carina Hanashima
    Smilow Neuroscience Program and Department of Cell Biology, Smilow Research Center, New York University, New York, New York 10016, USA
    J Neurosci 27:11103-11. 2007
    ....
  7. ncbi Perspectives on the developmental origins of cortical interneuron diversity
    Gordon Fishell
    Smilow Neuroscience Program, Department of Cell Biology, Floor Smilow Research Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA
    Novartis Found Symp 288:21-35; discussion 35-44, 96-8. 2007
    ..A primary challenge in the future will be to investigate what aspects of interneuron diversity are determined by intrinsic genetic programmes within each lineage versus those properties imposed by the local environment in the cortex...
  8. pmc The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes
    Simon J B Butt
    Smilow Neuroscience Program and the Department of Cell Biology, New York University, New York, NY 10016, USA
    Neuron 59:722-32. 2008
    ..Our strategy reveals a causal link between the embryonic genetic specification by Nkx2-1 in progenitors and the functional attributes of their neuronal progeny in the mature nervous system...