Cells destined to form the coronary vessels reside in the pro-epicardial organ (PEO) prior to migrating toe the developing heart tube. These cells form an epithelial layer over the heart and undergo epithelial- mesenchymal transformation and subsequent migration into the heart, followed by vessel formation. Similarly, the migration of neural crest cells into the heart is required for proper cardiogenesis, including coronary artery patterning and the septation of the outflow tract. We have shown that the Type III TGFb receptor (TBRIII) is required for epithelial- mesenchymal transformation and mesenchymal cell migration in the atrioventricular (AV) cushion of the heart. We will test the overall hypotheses that TBRIII is a mediator of epithelial-mesenchymal migration. We will use experimental embryological approaches in chick and genetic approaches in the mouse to gain a comprehensive understanding of the role of TBRIII in these events as they relate to coronary vessel development. Preliminary data in the chick demonstrate that TBRIII is expressed by both migrating neural crest cells and cells of the PEO. In addition, anti-TBRIII antisera inhibits the migration of neural crest cells in in vitro explant assays. The experiments we propose will determine the function of TBRIII in coronary vessel formation. The determination of which TGFb signal transduction complexes mediate cell transformation and cell migration will give general insight into TGFb signal transduction. Coronary vessel disease is a major cause of death in humans. A clearer understanding of coronary vessel development may identify novel approaches to treating coronary disease.
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