During the period of the past award, we have developed a transgenic mouse that targets Cre-recombinase to the epicardium. This is a unique model system that we have used to demonstrate that conditional mutation of the retinoid receptor alpha (RXR1) in the epicardium affects cardiac morphogenesis and impairs embryonic survival. This mutation also uncovered a novel role of nuclear receptors in coronary arteriogenesis. We have subsequently determined that the 2-catenin gene acts downstream of the RXR1 pathway and we have generated data demonstrating that mutation of 2-catenin in the epicardium impairs cardiac morphogenesis by reducing cardiac cell proliferation and coronary vessel formation. Here we hypothesize that a Wnt/2 catenin pathway in the epicardium regulates key steps in cardiac development, including cell proliferation in the myocardium and the formation of the coronary vasculature. To demonstrate this hypothesis, we propose three independent genetic approaches that address the following specific aims:
Aim 1 will determine the role of epicardial 2-catenin in cell fate specification and maturation of epicardial derivatives ex vivo and in vivo using time-lapse analysis of explanted tissues, lineage tracing, and mechanistic studies in epicardial-2-catenin mutant mice.
In Aim 2 we will determine whether Wnt activity regulates the formation of the coronary arteries and the expansion of the compact zone. To address this question, we will use a genetic strategy to block 2-catenin nuclear translocation and analyze signaling downstream of Wnt in the epicardium.. Finally, in Aim 3 we will determine whether 2 catenin is a functional mediator of RXR1 signaling. As a proof of principle for this hypothesis, we propose the rescue of the RXR1 phenotype by interbreeding the RXR1 mutant mice with the conditional 2 catenin/loxP (ex3) mouse, resulting in mice with constitutively active 2 catenin in the epicardium. Completion of this proposal will unravel the mechanisms of retinoid/2 catenin signaling in coronary formation and ventricular compaction and might offer the potential for therapeutic interventions to ameliorate or even treat coronary disorders that are leading causes of mortality.
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