We have identified an unusual population of neuronal progenitor cells that appear to regulate their cell cycle differently from other CNS progenitor/stem cells. The unusual progenitor cells migrate along a restricted pathway, the rostral migratory stream (RMS), from the anterior part of the forebrain subventricular zone (SVZa) to the subependymal zone (sez) in the middle of the olfactory bulb, and then migrate radially to become terminally postmitotic neurons of the granule cell and glomerular layers of the olfactory bulb. In contrast to other progenitor cells of the CNS, which become postmitotic before they migrate and differentiate, SVZa-derived cells with a neuronal phenotype migrate and repeatedly undergo division. This proposal will investigate whether the unique proliferative behavior of the SVZa-derived cells is due, in part, to the differential regulation of genes controlling cell cycle exit. In particular, based on our published and preliminary data, we hypothesize that SVZa-derived cells maintain the ability to sequentially express, and then down-regulate cyclin-dependent kinase inhibitors (CKIs), which are usually expressed when a neural precursor cell exits the cell cycle. Since an individual SVZa-derived cell may express more than one CKI as it traverses the RMS, we would like to determine how each CKI is involved, singly or cooperatively, in replicating SVZa-derived cells so that an appropriate number of olfactory bulb interneurons are generated. Preliminary evidence indicates that p19
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