NEGATIVE FACTOR WHICH REGULATES CARDIAC DEVELOPMENT

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An understanding of myogenesis and cardiac cell proliferation and differentiation must involve multiple, complex systems for controlling gene regulation during development. The cytoskeletal proteins, vimentin and desmin, provide an excellent model system for deciphering how genes are "turned-off" or activated during cardiac differentiation. Vimentin synthesis is first detected at the delineation of the mesoderm. A number of cell-types differentiate from this lineage and continue to synthesize vimentin, whereas others like heart "turn-off" the vimentin gene and activate the muscle-specific gene, desmin. The goal of this proposal is to determine what is required for the inactivation of the vimentin gene. Obviously, any defect in this early developmental decision could result in aberrant gene expression and compromise cardiac development. Previous work suggests multiple positive and at least one negative factor is required for vimentin expression in muscle tissue. The negative protein factor accumulates during embryogenesis which is responsible at least in part for turning-off the vimentin gene. This silencer protein appears early in chick heart development and increases 14-fold by day 18 in ovo. this increase roughly parallels the decline in vimentin mRNA which is barely detectable in chickens by six days of age. A comparable protein is found in mouse, rat and human cells and, therefore, it appears universal to most model developmental systems. Because the silencer protein is fairly abundant in heart, we suspect it is important for the regulation of other genes in addition to vimentin. In fact, it may also serve to coordinate cell growth and gene not clear whether or not myocytes are reversibly withdrawn from cell-cycle during development. The goal of this proposal is to characterize these cis-acting sequences and protein factors involved in vimentin gene regulation during cardiac development. Due to its novelty particular emphasis will be placed on the silencer protein. Here, positive factors involved in vimentin gene regulation and what other genes might be subjected to this regulation. Ultimately, we will isolate the silencer protein, its cDNA and gene. An understanding of how the silencer gene is regulated, is vital in determining how developmental decisions are made early in cardiac embryogenesis.