The long-term goal of the proposal is to understand the fundamental mechanisms that control development of the heart. Recently we have produced mouse embryos from embryonic stem (ES) cells in which both Gata4 and Gata6 genes, which encode zinc finger transcription factors, were simultaneously disrupted. Examination of these embryos revealed that cardiac myocyte differentiation was completely blocked and the resulting embryos exhibited acardia. Although these data are provocative we do not know i) whether this requirement for either GATA4 or GATA6 during the onset of heart cell differentiation is conserved in humans, ii) if the dependency of cardiac myocyte differentiation on both GATA4 and GATA6 reflects a cell autonomous role, or iii) whether redundant roles for GATA4 and GATA6 also exist for maintaining cardiac myocyte gene expression in terminally differentiated cardiac myocytes. We will answer these questions using a combination of genetic and molecular approaches using federally approved Human ES cells and transgenic mice. Success in the aims will further advance our understanding of the complex pathways that control heart development and function, which in turn will provide insight into the molecular basis of cardiac disease. PUBLIC HEALTH RELEVANCE: The current proposal is to address the role of two transcription factors GATA4 and GATA6 in controlling embryonic development of the heart. Success in the proposed goals will contribute to our understanding of the fundamental mechanisms that control formation of the cells that regulate contraction of the heart. This will provide insight into novel pathways that could be targeted by pharmaceutical or stem cell approaches to control cardiac pathologies.