REGULATION OF NEURAL GENE EXPRESSION

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The central aim of this proposed Program Project is to bring together individuals from a variety of disciplines to examine the expression of genes of neurobiological interest in order to understand their mode of action, regulation, and expression. It is clear that gene action can be regulated at a number of levels, which include transcription, RNA splicing, translation, and the post-translational processing/modification of proteins. It is also clear that agents such as hormones and growth/trophic factors, produced outside the nervous system (e.g. in the immune and endocrine systems) can regulate gene expression within the nervous system in important ways. Some of the consequences of this complex regulation by agents internal and external to the nervous system are: (a) the differentiation of precursors into cells with nervous system-specific functions, (b) proliferation and/or programmed death of groups of cells to give rise to specific anatomical and functional structures within the brain, and (c) the modulation of the production of important nervous system-specific proteins that result in modulation of cell function. A major goal of this proposal is to determine the mechanisms by which gene expression in neural cells is regulated in order to understand how function in the nervous system is regulated. Each project in this proposal is approaching the question of neural gene expression in the nervous system at a different level of investigation. The major objective of Project 1 will be to identify genes of importance in the functioning of the neostriatum, including putative genes that might involve Huntington's Disease. In Project 2, genomic elements that regulate the expression of two major myelin protein genes, myelin basic protein (MBP) and proteolipid protein, will be identified. In Project 3, elucidation of the multiple promoters of the MBP gene will be determined and the mechanism by which steroids influence the translation of the transcripts produced from those promoters will be determined. The focus of Project 4 will be to purify and clone a lymphocyte factor that induces the proliferation and differentiation of oligodendrocytes. In Project 5, the mechanisms by which steroids change the hypothalamic structure in the developing rat will be examined through the isolation and utilization of cDNAs specific for a sexually dimorphic nucleus in the brain. Collectively, these projects, which involve the cooperation and collaboration of the component research groups, seek to understand gene action at the molecular, cellular, and organismal levels.