The goal of the research is to define the inductive and patterning signals that specify the formation of cardiomyocytes in the embryo and to apply this information of the problem of cardiomyocyte regeneration. Preliminary data presented this application show that the secreted Wnt antagonists Dkk1 and Crescent are potent initiatory of Xenopus cardiogenesis in non-cardiogenic mesoderm. Additional results show that the cardiomyocyte differentiation is restricted to a portion of the heart/NKx2.5 field by suppressive signals from neurogenic tissue and by local cell-cell interactions mediated by Serrate and Notch. These signals, in conjunction with BMP, appear sufficient to promote cardiomyocyte differentiation in embryonic mesoderm. Three broad objectives are proposed. The first is to determine whether Wnt antagonists act directly on prospective cardiac progenitors or if they induce an intermediary factor in another tissue, such as the endoderm underlying the cardiac primordial. Although endoderm is essential for heart induction, the inducing proteins it produces are known. Therefore, a cDNA expression screen seeks to identify these factors from a dorsoanterior endoderm cDNA library. The second objective is to identify the type of neurogenic cells that restrict cardiomyocyte differentiation to the ventral portion of the Xenopus heart/Nkx2.5 field. Studies will then determine whether the neurogenic signal regulated cardiomyocyte differentiation through Notch and BMP signaling. Lastly, the third objective is to apply the knowledge of embryonic heart induction to cardiomyocyte regeneration. Experiments will assess the cardiomyogenic potency of a promising class of stem cells that are FACS purified from bone marrow and differentiated tissues. Factors that reside in the embryonic heart-forming region, such as Dkk1, Crescent and novel proteins secreted by the endoderm, will be tested for the ability to enhance myocardial differentiation of these cells in vivo.
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