MYOCYTE PROLIFERATION IN THE EMBRYONIC CHICK HEART

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The withdrawal of embryonic cardiac myocytes from DNA-synthesis, and factors controlling this key event in myocardial growth and differentiation, will be studied in normal and experimentally altered hearts of embryonic chicks. Labelling studies in both chicks and rates have defined regional differences in DNA-synthetic activity within the embryonic tubular heart that suggest the following hypotheses: 1) the commitment to non-proliferation is a key step in initial determination of cardiac laterality and looping; 2) quiescent myocytes massed along the inner curvature of the looped tubular heart and extending along the earliest ventricular trabeculae are the precursors of ventricular conducting tissue; newly quiescent cells are recruited to the periphery of this trabecular network from the inner layers of the ventricular free walls. Specific experiments will address the following questions: 1) When and where do such quiescent myocytes first appear (marking and mapping experiments) ? Is the timing and distribution of such cell populations altered in models of reversed laterality (retinoic acid gradients or cytochalasin crystals in cultured chicks)? 2) Can the commitment to non-proliferation be correlated with known markers of conducting tissues (correlative immunostaining, in situ hybridization, EM/autoradiography for growth factors, homeobox genes 7 & 8, cardiac connexins)? Does the commitment to non-proliferation occur at the periphery or core of the trabecular network and is this commitment sudden or gradual? 3) How is myocyte proliferation altered by retroviral infection and expression of truncated or anti-sense sequences for genes specifically correlated with normal quiescence (homeobox-8 or connexins)? Experimental answers to these studies will test the hypotheses stated above and further our long-range objective of describing vertebrate cardiac development in detail sufficient to understand and eventually prevent congenital heart disease in the human.