MYOCYTE PROLIFERATION IN THE EMBRYONIC CHICK HEART

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DESCRIPTION (adapted from the applicant's abstract): Proliferation, terminal differentiation and eventual fate of specific populations of cardiac myocytes will be studied in 1) the conduction system of the normally developing chick heart, 2) in an in vitro muscular tube preparation, and 3) in chick embryos provoked to specific cardiac malformations. Recent studies have identified earliest terminal differentiation in chick heart during initial looping and traced the contribution of such early trabecular and inner wall myocytes into the definitive central conduction system of the fully-formed heart. Some cells labeled on days 2-3 of incubation remain labeled at least 100 days post hatching; some of the branches of the embryonic conduction system disappear through apoptotic cell death during the septation period. These studies are the basis for the central hypothesis of this proposal, that early terminal differentiation of specific populations of cardiac myocytes during looping and septation is critical both to the emergence and proper formation of cardiac conduction tissue and to normal morphogenesis of the definitive four-chambered heart. The principal investigator now proposes a five-year program of experiments to: Aim 1) Map the emergence of cardiac conduction tissue in terms of spatial and temporal patterns of terminal differentiation and persistence of specialized progenitor populations of inner wall myocytes. Aim 2) Explore effects of altered geometry and physical load conditioning upon myocyte proliferation and terminal differentiation in artificial myocardial tubes and prelooping hearts cultured in vitro. Aim 3) Compare three widely divergent chick models of ventricular septal defect to test for common variation in the normal patterns of conduction tissue disposition and terminal differentiation established above. These experiments are designed to test specific hypotheses concerning 1) the physical factors underlying the formation and maturation of the conduction system, 2) the decision of embryonic cardiac myocytes to proliferate, terminally differentiate, or die; and 3) potentially common variations in such patterns in widely differing models of cardiac malformation.