Epicardial retinoid X receptor α is required for myocardial growth and coronary artery formation

Vitamin A signals play critical roles during embryonic development. in particular, heart morphogenesis depends on vitamin A signals mediated by the retinoid X receptor alpha (RXR alpha), as the systemic mutation of this receptor results in thinning of the myocardium and embryonic lethality. However, the molecular and cellular mechanisms controlled by RXR alpha signaling in this process are unclear, because a myocardium-restricted RXR alpha mutation does not perturb heart morphogenesis. Here, we analyze a series of tissue-restricted mutations of the RXR alpha gene in the cardiac neural crest, endothelial, and epicardial lineages, and we show that RXR alpha signaling in the epicardium is required for proper cardiac morphogenesis. Moreover, we detect an additional phenotype of defective coronary arteriogenesis associated with RXR alpha deficiency and identify a retinoid-dependent Wnt signaling pathway that cooperates in epicardial epithelial-to-mesenchymal transformation.