Increasing evidence indicates that insulin-like growth factor-I (IGF-I) plays an important role in the development of neural cells in the central nervous system, including oligodendrocyte lineage cells and myelination, as well as promoting regeneration of oligodendrocyte lineage cells following injury. We hypothesize that IGF-I acts directly on the cells of oligodendrocyte lineage by mechanisms that are initiated by interaction with its cell surface receptor, the type 1 IGF receptor (IGF1R), and in turn by regulation of gene expression. Our hypothesis is supported by our data and those of others showing that: 1) IGF-I promotes proliferation and differentiation of oligodendrocyte lineage cells in culture; 2) overexpression of IGF-I in transgenic (Tg) mice during postnatal development increases the number of oligodendrocyte lineage cells; 3) in animals subjected to demyelinating insults, the expression of IGF-I and IGF1R genes is induced in a fashion temporally and spatially related to the injury; 4) IGF-I protects myelination from a variety of CNS injury; and 5) blunting IGFIR expression specifically in oligodendrocytes results in brain retardation and hypomyelination in the mutant mice. Furthermore, our recent studies show that IGF-I regulates multiple gene expression and modification of histone proteins in cells of oligodendrocyte line. In this application, we propose two specific aims to further examine our hypotheses: 1) To determine IGF actions on the development of oligodendrocyte precursors in vivo, we will examine oligodendrocyte precursors in newly developed Tg mice that overexpress IGF-I during embryonic and early postnatal development, and in mutant mice in which IGF1R expression is specifically blunted in oligodendrocyte precursors. 2) To delineate IGF-I signaling mechanisms leading to the gene regulation that promotes oligodendrocyte development, we will determine a) IGF-I in vivo regulation of global gene expression in oligodendrocytes and their precursors using laser captured microdissection and DNA array; and b) IGF-I actions on chromatin remodeling. ? ? ?
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