REGULATION OF CARDIAC MYOGENESIS

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Heart muscle is among the earliest differentiated tissues to appear in the developing embryo because a functioning heart is crucial to embryonic development and viability. We know surprisingly little, however, about how the heart forms, or about the mechanisms that regulate discrete steps along the pathway of heart muscle cell specification, proliferation and differentiation. In large part, our lack of knowledge can be traced to the absence of in vitro cell models that can recreate key aspects of heart muscle cell development. We have recently developed two in vitro culture assays that will enable us to address important questions concerning early heart development. Accordingly, the research in this proposal will use these assays to investigate how cellular interactions and growth factor signaling molecules regulate the appearance of heart muscle precursor cells in the avian embryo. One assay utilizes explants of posterior marginal zone epiblast and hypoblast from pregastrula embryos, the second uses discrete areas and cell layers within the primitive streak and Hensen's node of early gastrulae. Based upon preliminary studies, we have proposed that heart muscle precursor cells become specified in response to growth factor signals from surrounding cell layers and tissues, including the hypoblast, Hensen's node and emerging endoderm. Experiments will test this proposition by investigating the inductive interactions between responding and inducing cell layers that lead to the appearance of specified premyocardial cells, and by searching for growth factors that can induce heart muscle in responsive cell layers. Experiments will also investigate the potential role of newly formed endoderm in regulating development of heart muscle precursor cells, and will investigate how Tinman (Nkx-2,5) and MEF2 gene expression is regulated during specification of precardiac mesoderm. Results of these studies will increase our understanding of both normal and abnormal heart development and may suggest ways to alter heart development or the replication of cardiac myocytes.