Wdpcp promotes epicardial EMT and epicardium-derived cell migration to facilitate coronary artery remodeling

During coronary vasculature development, endothelial cells enclose the embryonic heart to form the primitive coronary plexus. This structure is remodeled upon recruitment of epicardial cells that may undergo epithelial-mesenchymal transition (EMT) to enable migration and that give rise to smooth muscle cells. In mice expressing a loss-of-function mutant form of Wdpcp, a gene involved in ciliogenesis, the enclosure of the surface of the heart by the subepicardial coronary plexus was accelerated because of enhanced chemotactic responses to Shh. Coronary arteries, but not coronary veins in Wdpcp mutant mice, showed reduced smooth muscle cell coverage. In addition, Wdpcp mutant hearts had reduced expression of EMT and mesenchymal markers and had fewer epicardium-derived cells (EPDCs) that showed impaired migration. Epicardium-specific deletion of Wdpcp recapitulated the coronary artery defect of the Wdpcp mutant. Thus, Wdpcp promotes epithelial EMT and EPDC migration, processes that are required for remodeling of the coronary primitive plexus. The Wdpcp mutant mice will be a useful tool to dissect the molecular mechanisms that govern the remodeling of the primitive plexus during coronary development.