The molecular mechanisms by which embryonic cells fromthe mesoderm become the heart are not well understood. It has been found that cardiogenesis requires the combination of at least two factors: an anterior endodermal factor, Crescent, and a BMP signal from the lateral ectoderm and endoderm. Crescent is related to a family of proteins which serve as Wnt inhibitors. In this proposal, I hope to demonstrate the molecular mechanism by which Crescent promotes and Wnt signals block the formation of cardiac myocytes. To address this, it will be determined whether Wnt blocks cardiogenesis in the chick embryo through a LEF-1/Tcf- dependent mechanism. If so, it will then be determined whether a dominant-negative form of LEF-1/Tcf can mimic the cardiac- inducing activity of Crescent in posterior mesodermal tissues. Finally, it will be determined whether Crescent, or other factors which oppose the Wnt pathway, can act synergistically with BMP signals to induce cardiogenesis in adult hematopoietic stem cells. Thus, I hope to contribute to the molecular understanding of how the cardiac myocyte differentiation program is activated during vertebrate development. Ultimately, by understanding the fundamental mechanisms by which cardiac specification occurs in the embryo, it may be possible to manipulate and re-specify the programming of adult cells to form cardiomyocytes. This would allow the generation of cardiomyocyte stem cells for the potential use in cell transplantation therapy to improve the contractility of the failing heart.
