REGULATION OF ATRIOVENTRICULAR CANAL MESENCHYME FORMATION

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Development in the atrioventricular canal of the embryonic heart is characterized by an endothelial-mesenchymal cell transformation of a subpopulation of endothelial cells. These cells change phenotype to become invasive mesenchymal cells and are the earliest progenitors of valve and septal structures in the heart. Through use of collagen gel cultures of embryonic chicken material, we and others showed that the transformation process is stimulated by a signal from the myocardium and is both regionally and temporally specific. Preliminary studies had identified a growth factor, TGFbeta, as a component of the transformation process. During the previous grant period we showed TGFbeta3, among the members of the TGFbeta family, to have an appropriate distribution within the heart. Further, reduction of TGFbeta3 mRNA levels by treating heart explants with modified antisense oligonucleotides confirmed a direct role for this molecule in the avian heart. We have also identified an mRNA that may hybridize to TGFbeta3 encoding transcripts within the heart. This antisense RNA has a distribution and appearance consistent with a role in regulating TGFbeta3 message translation. Additional studies were performed to begin to address the process of cell transformation by identifying signal transduction and gene expression in the target endothelial tissue. Continuing studies are proposed here to explore cell transformation in the heart and the regulation of TGFbeta3 in this process. The specific aims of the proposal are to: l) Analyze TGFbeta3 message and protein production during cushion tissue formation. 2) Characterize antisense TGFbeta3 mRNA in the heart and, if appropriate, its protein product. 3) Characterize the activation signals which regulate antisense TGFbeta3 transcription. 4) Examine expression of signal transduction molecules and additional molecules identified within this SCOR which can be directly related to valve formation or related morphogenetic processes in the embryonic heart. These studies will define the role of TGFbeta3 and its regulation in the differentiation of cardiac valvular and septal mesenchyme. The goal of this work is to understand the molecular signals involved in this process of induced phenotypic change. An understanding of these processes will provide both basic developmental principles and identify candidate genes and interactions involved in congenital heart disease.