Vitamin A and its metabolites (retinoids) play a critical role in cardiac morphogenesis. Retinoids are potent human teratogens linked to several types of birth defects, including cardiovascular anomalies, while vitamin A deficiency can produce ventricular chamber hypoplasia, ventricular septal defects, and aortic abnormalities. A mutation in a single members of the retinoid receptor family (RCRalpha) reproduces many of the cardiovascular defects seen in vitamin A deficient embryos.
The specific aims of the present proposal will capitalize on recent advances in CRE- lox technology ti specifically mutate the RXRalpha gene within specific cardiovascular cell type compartments during in vivo cardiac development: 1) to determine the role of RXRalpha pathways within atrial and ventricular muscle cells in control of cardiovascular morphogenesis by creating mice which harbor an early, complete atrial and ventricular muscle cell lineage restricted deficiency in RXRalpha via CRE-lox technology; 2) to determine the role of RXRalpha pathways within cardiac neural crest cell lineages in the control of cardiovascular morphogenesis by creating embryos which harbor a neural crest cell lineage restricted deficiency in RXRalpha; 3) To determine the role of RXRalpha pathways within endothelial/endocardial cushion cell lineages in cardiovascular morphogenesis by creating mice which harbor an endothelial cell lineage restricted deficiency in RXRalpha; 4) To determine the role of all retinoid receptor dependent pathways in specific cardiovascular cell types (atrial muscle, ventricular muscle, endothelial, and neural crest) in cardiovascular morphogenesis by creating mice which conditionally express a dominant negative retinoid receptor in specific cardiovascular cell types via a Cre-lox switch strategy. These studies should lead to the definitive identification of the specific cardiovascular cell types that generate the RXRalpha dependent signals required for specific steps in cardiac morphogenesis. Since mutations in a number of transcription factors have been implicated in human congenital heart defects, these studies of RXRalpha could lead to establishment of a new paradigm by which an individual transcription factor may be required in distinct cardiovascular cell types at precise stages of cardiogenesis to provide the molecular cues that lead to complex steps of cardiac morphogenesis.
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