Congenital heart defects resulting from abnormal cardiac development comprise a significant proportion of congenital diseases. Gene ablation studies in mice have demonstrated that signaling by the secreted growth factor bone morphogenetic protein (BMP) is required for a number of aspects of heart formation which are perturbed in congenital heart disease. We have recently demonstrated that BMP signaling is required for cardiac specification and heart formation in vertebrates. However, the critical time and spatial requirements for BMP signaling to effect cardiac specification and specific aspects of cardiac morphogenesis have not yet been determined. Although BMP signaling is required for a number of aspects of heart formation, an intriguing observation is that an inhibitor of BMP signaling, Smad6, is highly expressed in cardiogenic regions. This observation suggests that excessive BMP signaling is deleterious to cardiogenesis. Following from these observations, our hypothesis is that BMP signaling is required sequentially, in a measured and spatially distinct manner, thoughout cardiogenesis to affect specific aspects of heart formation and development. Several aspects of Xenopus as a model system render it an ideal system with which to test this hypothesis. We will capitalize on the strengths of Xenopus by utilizing stable transgenesis and a gluococorticoid inducible system to block or increase BMP signaling at distinct time periods and in specific tissues during cardiogenesis, and examine consequent effects on a number of parameters of heart development. To perform these studies, we will pioneer Cre-mediated recombination in Xenopus. Development of this technology should have far-reaching impact for future studies of cell and organ fate decisions in frogs, and will make possible experiments which are currently not possible in other systems.
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