Signaling and transcriptional control of brain development involves precise programs of gene repression and activation that are required to maintain the neural stern cell phenotype and establish specific neuronal phenotypes. The central theme in our laboratory under this grant has been to define the transcriptional mechanisms by which nuclear receptors and POU domain transcription factors, via recruitment of corepressors, function in development of the central nervous system. During the current grant period we have cloned and characterized a series of novel genes that are components of corepressor and coactivator complexes associated with nuclear receptors and POU domain factors. Genetic approaches have revealed the specific roles of N-CoR and its regulation by specific signaling pathways and the connection between a novel N-CoR complex and the actions of inflammatory signals, and has provided general insights into molecular mechanisms of regulation of receptor and POU domain factor function in neuronal development, and revealed an unexpected mechanism into intracellular partitioning of corepressors. The central focus of the current proposal is to investigate the mechanisms by which specific corepressor and coactivator complexes serve to integrate the transcriptional responses to distinct signaling pathways, using neural stem cells and differentiation of neurons and glia as a model. We will define the functional roles of specific components of the corepressor complexes both in gene repression and gene activation events, and we will examine the link to specific neurodegenerative diseases using genetic, genomic, and molecular biological/biomedical approaches. These studies will expose the roles of specific components of the diverse N-CoR/SMRT complexes in regulation of precursor cell proliferation and the roles of specific repressor/corepressor complexes in regulation of chromatin silencing events in early neurodevelopment. We will investigate a potential link between displacement of specific corepressor complexes in murine models of a neurodegenerative disease, and the molecular mechanism underlying the exchange of coactivator complexes. These studies will provide insights into the molecular mechanisms underlying control of gene transcription that are required for maintaining the neural stem cell state and for establishing specific neuronal phenotypes. ? ?
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