A critical question in biology is how stem and progenitor cells integrate multiple signals from their environment to make decisions to proliferate or to exit the cell cycle and differentiate. The oligodendrocyte lineage has been the focus of numerous studies on how specific growth factors including platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2) and insulin-like growth factor-I (IGF-I) regulate the generation of oligodendrocytes. Our previous studies demonstrated that 1) IGF-I is required for maximal stimulation of oligodendrocyte progenitor cells (OPCs) by PDGF and FGF-2, 2) IGF-I and FGF-2 are synergistic in promoting DNA synthesis in OPCs, and 3) IGF-I, in the presence of FGF-2, increases recruitment of OPCs into the cell cycle. The immediate goals of this proposal are to test the hypotheses that 1) IGF-I, FGF-2 and PDGF coordinately regulate cell cycle progression in OPCs by inducing specific molecular components of the cell cycle, and 2) IGF actions through the IGF type I receptor (IGF-IR) are essential for maximal OPC proliferation. To test the first hypothesis, experiments are proposed to determine how PDGF, FGF-2 and IGF-I coordinate to amplify the induction and activation of the cyclin-cyclin-dependent protein kinases that are essential for G1, S and G2 progression in the OPC. To test the second hypothesis, we will investigate the function of endogenous signaling through the IGF-IR in OPCs in vitro and in vivo using ribozyme technologies and transgenic approaches to inhibit IGF-IR expression and activation. The data from these studies will be important to our understanding of cell cycle regulation in the OPC and will be of broader interest to the field of signal integration in progenitor cell proliferation during development. Moreover, the investigations proposed here will provide the basis for understanding the mechanisms by which proliferation of adult oligodendrocyte progenitors could be enhanced to promote repair of demyelinating lesions in central nervous system disorders such as Multiple Sclerosis. ? ?
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