Regulation of neurogenesis in the cerebellum

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DESCRIPTION (provided by applicant) A fundamental aspect of developmental neurobiology that we still do not fully understand is how positional information coordinates with local regulation of neurogenetic programs to establish specific patterns in the brain. In vivo, the issue is experimentally accessible in the cerebellum. Inbred mice strains show complex yet invariant patterns of cerebellar foliation that is underpinned by a simple laminar structure comprised of a limited number of defined neuronal subtypes, facilitating characterization of the underlying mechanisms regulating neurogenesis. Examining defects in patterning of cerebellar cortex using mutant mouse models has confirmed that cerebellar patterning is intimately tied to the differentiation program of the neuroblasts, but how regulation occurs is still unclear. Our preliminary results suggest that certain molecules crucial for regulating membrane/cytoskeletal interactions during axon guidance also play important roles in regulating the neurogenic response to patterning information. One of these is the nervous system-specific protein GAP-43. We already know that GAP-43 is required in order for differentiated neurons to respond to signals that give rise to patterning in the CNS. For example, our GAP-43 knockout mouse fails to form either topographic maps in cortex, or telencephalic commissures, because in both cases GAP-43 (-/-) neurons are unable to respond to immunoglobulin superfamily (Ig-SF) mediated axon outgrowth and guidance signals. However the GAP-43 (-/-) mouse also has severe defects in cerebellar patterning that are evident before axonogenesis but during the time that neurogenesis is being regulated by extracellular patterning programs. The objective of this FRICA grant is to understand the molecular mechanisms underlying the disruption of patterning in the cerebellum that occurs when GAP-43 is absent. We describe 3 experiments: First, to determine the earliest stage of cerebellar development that requires GAP-43 function. Second to investigate whether 2 known neurogenic regulators in the cerebellum (bFGF and BDNF) can function when GAP-43 is absent - we already know that bFGF requires GAP-43 and that BDNF can stimulate GAP-43 phosphorylation in growing axons. Finally we will characterize how absence of GAP-43 affects transduction of lg-SF signals that regulate the cell cycle in differentiating cerebellar neurons. This research will be performed primarily in India as an extension on NIH grant# RO1 NS33118.