An understanding of the molecular mechanisms that are required for cardiomyocyte cell fate decisions is critical for uncovering the pathologies and treatments for congenital heart disease. To address these issues, we have cloned and characterized the vertebrate orthologues of the zinc finger transcription factor, Castor (Cst). We have gone on to show that in Xenopus Cst is in required for cardiomyocyte differentiation;in the absence of Cst, cells at the ventral midline retain early cardiac progenitor fate but are blocked from differentiating into cardiomyocytes. The role of Cst is further emphasized by recent genome-wide association studies showing a genetic link between Cst and high blood pressure and hypertension. The overall goal of this proposal is to elucidate the cellular and molecular mechanism by which CST functions. To address these issues we have generated a set of unique alleles of Cst in mouse and will now use these alleles to determine the requirement and fate of Cst expressing cells in cardiac development. In addition, to address the molecular mechanisms by which CST functions in heart development, our lab has undertaken a set of approaches to identify the CST transcriptional complex. From these studies we have demonstrated that CST directly interacts with the congenital heart disease associated protein (CHD5), a protein initially cloned and identified from the minimal region containing the gene responsible for congenital heart disease in Down Syndrome patients. Moreover, we have used a directed proteomic-based approach to show that CST and CHD5 directly associate with the Nucleosome Remodeling and Deacetylase (NuRD) complex including histone deacteylase-1 and 2 (HDAC1/2). Based on our findings, we hypothesize that Cst functions as a transcriptional repressor which is required for early cardiac cell fate decisions. To test this hypothesis we will a) determine the fate and requirement of Cst-expressing cells to the developing heart, b) define the core components of the Cst-NurD transcriptional complex and c) determine the role of CHD5-CST interaction in regulating CST activity.

Public Health Relevance

Clinical and genetic studies in model organisms have provided direct evidence for the role of CASTOR (CST) in heart development and human disease. However, almost nothing is known about how CST functions. This proposal will provide insight into the general mechanisms of CST function, define the mode of action of CST in human disease, and identify additional potential candidate genes associated with human congenital heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Schramm, Charlene A
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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