Significant progress has been made over the last decade in our understanding of the transcriptional regulation of cardiac development. Such progress has led to insights into the molecular mechanisms of congenital heart disease and has implications for our understanding of cardiomyocyte stem cells. To date, work in the field of cardiac development has focused on transcriptional activators and their role in cardiogenesis. Recent progress in developmental biology indicates that transcriptional repressors are also critical for a number of developmental events including heart formation. FOG-2 is one such transcriptional co-repressor that we have previously shown is required for cardiogenesis. FOG-2 is first expressed at murine embryonic day 8.5 in the developing heart tube and physically associates with the transcriptional activator GATA4. Mice deficient in FOG-2 die in mid-gestation of heart failure secondary to cardiac malformations. These malformations include a common atrioventricular valve, pulmonic stenosis, an atrial septal defect, and left ventricular wall hypoplasia. In this proposal, we outline further research to define the transcriptional pathway utilized by FOG-2 to regulate cardiogenesis. Specifically, we propose to (1) characterize an alternative transcript of the FOG-2 gene, (2) identify the upstream regulators of FOG-2 gene expression, and (3) determine genes that are downstream in the transcriptional pathway regulated by FOG-2. The results of such work will further define the transcriptional hierarchy orchestrating heart formation and may lead to the identification of novel transcriptional regulators of cardiac development. Further, this work may also lead to novel insights into the molecular basis for congenital heart disease and may define a general paradigm for the role of FOG family members in other cell and developmental contexts.
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