The ability of specific hormones to influence developmental processes has been amply documented, however, the analysis of underlying mechanisms has been severely compromised by the complexity of the systems being studied and the difficulty in obtaining pure populations of cells that undergo differentiation under controlled conditions. Moreover, those of us interested in vertebrate systems have not had the benefit of genetic approaches to help in dissecting the complex regulatory networks that dictate the timing and implementation of developmental decisions. In somewhat anthropomorphic terms, the central theme of this proposal surrounds the following question. What are the biochemical signals that instruct """"""""determined"""""""" cells to not express differentiated functions at inappropriate times and (2) how does the cell sense the environmental cues that instruct it to activate a specified set of tissue-specific genes? It is the nature of this triggering process and the roles that various classes of hormones play in regulating the decision to differentiate that is the focus of our studies. Specifically, we will pursue studies aimed at understanding the mechanisms by which: 1) glucocorticoid hormones accelerate the differentiation of adipogenic cells and 2) certain growth factors (notable FGF and PDGF) prevent differentiation. Major emphasis will be placed on characterizing the regulation and the function of the glucocorticoid-inducible and FGF/PDGF-repressible AP27 gene, the product of which appears to play a key role in triggering the differentiation of TA1 and 3T3-L1 adipocytes. In addition we will attempt to delineate the cis-acting elements and transcription factors that are crucial for regulating the expression of a gene (clone 47/FSP27) that is transcriptionally activated only in differentiated adipocytes. It is among these regulatory factors that we imagine the targets(s) for the hormonal signals ultimately reside. Our goal is to elucidate the pathways that hormonal signals utilize to alter the ability of cells to undergo differentiation. Complex interactions between the growth state of the cell and such hormonal signals will play a prominent role in our studies. We anticipate that the approaches we are taking will help to elucidate fundamental aspects of tissue-specific gene expression, the biochemistry of cell differentiation, and the regulatory networks established by hormonal signal
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