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Proper development of the nervous system requires a balance between proliferation of neuronal precursors and differentiation of these cells into neurons. This balance is particularly striking in the case of cerebellar granule cells, the most abundant neurons in the brain and a critical component of the circuitry that controls motor coordination. When granule cell precursor proliferation is disrupted and not enough granule cells are generated, cerebellar dysfunction and ataxia may result; when granule cell differentiation fails, cells that would normally become post-mitotic continue to proliferate and may give rise to cerebellar tumors. Therefore, elucidating the molecular mechanisms that control growth and differentiation is critical for understanding both normal cerebellar development and tumorigenesis. Our previous studies (Wechsler-Reya & Scott, 1999) have demonstrated that proliferation of granule cell precursors (GCPs) is controlled by the secreted signaling molecule Sonic hedgehog (Shh). But the signals that cause GCPs to stop proliferating, differentiate and migrate remain a mystery. Using both primary cell culture and transgenic mouse models, we are investigating the role of fibroblast growth factors, netrins, chemokines and other signals in granule cell development. For a recent example of our research in this area, see Fogarty et al., 2007.
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