Development of the endocrine hypothalamus involves the formation of specific nuclei, characterized by production of specific neuropeptides, in which phenotypes of component cells appear in a spatially distinct fashion. These nuclei are regulated by the actions of nuclear receptors and by class III POU domain factors, and also by the actions of specific signaling molecules. In the current grant period, the applicant investigated transcriptional control of terminal differentiation of the endocrine hypothalamus and identified several novel factors hypothesized to serve as specific nuclear receptor coregulators. A ligand-dependent switch of a histone deacetylase-containing corepressor complex for a histone/factor acetyltransferase containing coactivator complex was suggested, and several structural aspects of the underlying protein-protein interactions were defined. In this competitive renewal, the applicant proposes to begin to elucidate the putative signaling gradients that may be required for the sequential determination and differentiation events that mediate the generation of specific cell phenotypes in the endocrine hypothalamus. The potential combinatorial roles of a family of related transcriptional factors in early and late developmental events in the hypothalamus will be defined, as will the physiological role of several novel factors. The in vivo role of specific components of nuclear receptor corepressors and coactivators will be explored, and their regulation will be analyzed. The role of a novel type of """"""""cosynergy"""""""" factor that may alter function of the enzymatic activities in the coactivator complex will also be examined. It is predicted that these investigations should permit further insights into both the molecular mechanisms by which the endocrine hypothalamus is established and the molecular mechanisms by which ligand-dependent transcription factors exert their positive and negative effects on gene expression.
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