EXCEED THE SPACE PROVIDED. Development of neurons, such as those of the endocrine hypothalamus invoves regulation by the actions of nuclear receptors and by other classes of transcription factors, such as the Class III POU domain factors, as well as the actions of specific signaling molecules. The initial five years under this Merit Award have proven to be our most productive and innovative cycle under this Grant. We have contributed a series of discoveries concerning the molecular mechanisms by which nuclear receptors mediate gene repression and activation events and that have established a new paradigm concerning the molecular mechanisms of gene regulation. Our central theme in our laboratory under this grant has been to define the molecular mechanisms by which nuclear receptors, POU domain factors, and other classes of transcriptionfactors function via recruitment of corepressors and coactivators, and to define a role for these factors in establishing neuronal and other cellular phenotypes and in regulating function. We have identified novel molecular mechanisms that regulate tissue- and cell type-specific proliferation and activation, and defined roles for corepressors in these events. We will investigate the molecular basis of action of components of the TBLR1/TBL1/GPS2/ HDAC3 complexes, investigating the potential roles of GPS2 as an inhibitor of specific protein kinases, and the roles of site-specific phosphorylation of N-CoR/TBLR1 and TBL1 in the required recruitment of specific ubiquitin ligase 19S proteasome machinery using neuronal models. The relationship of these factors to the actin-related complexes that may detect nuclear localization and alterations in chromatin structure will be defined
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