The long-term goal of this research proposal is to understand the developmental mechanisms of CNS progenitor differentiation. More specifically the focus of this grant is to elucidate the mechanisms responsible for the transition from the late progenitor stage to terminal differentiation. Using the oligodendrocyte (OL) lineage as model system, this experimental plan tests the hypothesis that histone deacetylation is a crucial event during this transition. The model being tested is that """"""""activation"""""""" of the OL differentiation program occurs through a de-repression mechanism, mediated by histone deacetylation. This model implies that progenitors are maintained in an undifferentiated state by """"""""inhibitory"""""""" mechanisms that prevent the cytoskeletal changes and the pattern of gene expression characteristic of the mature phenotype. The transition to terminal differentiation is characterized by disinhibition of these mechanisms due to histone deacetylation.
Specific Aim 1 tests the hypothesis that histone deacetylation is essential for decreasing the expression of microtubule (i.e. stathmin) and microfilament (i.e. gelsolin) severing proteins which are important for the morphological changes characteristic of terminally differentiated oligodendrocytes.
Specific Aim 2 tests the hypothesis that histone deacetylation contributes to the myelin gene activation DIRECTLY, by compacting chromatin in the negative regulatory regions of their promoters.
Specific Aim 3 tests the hypothesis that histone deacetylation contributes to activation of myelin gene expression INDIRECTLY, by regulating chromatin compaction in the promoter region of genes encoding inhibitory molecules. The results of these studies are expected to have broad implications for the current concept of developmental regulation of gene expression and also for remyelination therapies in multiple sclerosis and after CNS injury. Furthermore, by addressing the regulation of genes whose expression is altered in glial tumors, they may contribute to the general knowledge of neoplastic transformation of glial progenitor.
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