REGULATION OF CARDIAC MYOGENESIS

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An understanding of the molecular regulation of heart muscle cell development is an important prerequisite to understanding how heart defects arise during embryonic development. Although much has been learned in recent years concerning the transcriptional regulation of cardiac gene expression, less is known about signaling interactions that regulate steps along the pathway of heart muscle cell specification, proliferation and differentiation. We have developed assays in avians to investigate the earliest signaling interactions involved in development of cardiac myocyte development. Using these assays, signaling interactions and signaling molecules have been identified that regulate important steps in heart muscle cell development. From these studies we have proposed that signals from both the hypoblast and anterior lateral endoderm are required for the appearance of differentiated heart muscle cells. Signaling molecules have also been identified that are produced by the hypoblast initiate heart muscle cell development in the epiblast. The goals of this project are to more clearly define tissue interactions and signaling molecules regulating cardiac myocyte development in avians, and to use that information to begin investigating the earliest stages of cardiac myogenesis in mouse. Studies will investigate signaling interactions regulating mesoderm development in pregastrula and gastrula stage mouse embryos using microsurgical, explanation and recombination techniques. Experiments will test the hypothesis that signals from both visceral endoderm and anterior lateral endoderm are required for cardiac myogenesis in mouse. Experiments will also investigate the role of several types of signaling molecules in mammalian cardiac myogenesis, including fibroblast growth factors, activin, transforming growth factor beta, and the epidermal growth factor related molecule cripto-1. Finally experiments will investigate how expression of the homeobox gene Hex in anterior lateral endoderm regulates later stages of cardiac myogenesis. This information will increase our understanding of both normal and abnormal heart development and may suggest ways to alter heart development or replication of cardiac myocytes.