Complex brain function depends on interactions among diverse neurons comprising the nervous system. Our long term goal is to define mechanisms regulating production of different neuronal cell types. During ontogeny, neurogenesis proceeds in region-specific fashion, producing cerebral cortex neurons prenatally and cerebellar granule cells postnatally. While extracellular factors, including bFGF and IGF-1, stimulate precursor proliferation, virtually nothing is known about mediating cell cycle mechanisms. We plan to use a well-defined cortical precursor model, and cerebellar granule cells, to characterize roles of pro-mitogenic (cyclins and CDKs) and antimitogenic (INK4 and CIP/KIP inhibitors) cell cycle regulators in mitogenic stimulation. Specifically, we will define (a) bFGF Effects on Proliferation and Cell Cycle Machinery of Prenatal and Postnatal Precursors In Vitro, (b) IGF-1 Effects on Proliferation and Cell Mitogens in Proliferation In Vivo, (d) Effects of Genetically Manipulating Cell Cycle Regulators on Mitogen-lnduced Proliferation. Studies will examine mitosis, proliferation, flow cytometry, western and kinase analyses, and genetic mutants and transfection strategies, used in culture and in developing animals. By characterizing region- and stage-specific roles of bFGF and IGF-1, we may identify growth factorspecific signaling underlying production of distinct prenatal and postnatal neuronal populations during development. In turn, we may gain insight into extra- and intracellular pathways underlying deficiencies of select neuronal systems, potentially contributing to developmental diseases, such as schizophrenia, cerebral palsy and autism.
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