Morphogenesis of the muscular ventricular septum of the mouse heart is driven by retinoic acid signalling to myocardium

The mammalian heart is divided into four chambers by septa that isolate systemic and pulmonary circulation and are hotspots of congenital heart defects (CHD). The muscular ventricular septum develops between left and right ventricular cardiomyocytes derived from the first and second heart fields. Despite its clinical importance, mechanisms underlying development of the ventricular septum are poorly understood. Here we show that myocardial reception of retinoic acid (RA) signalling regulates formation of the compact septal core. Activation of a dominant negative RA receptor in second heart field-derived myocardium during septal morphogenesis results in a deep interventricular cleft and bifid cardiac apex. This phenotype is preceded by ectopic trabecular contributions to a RA-independent septal primordium. Molecular analysis implicates defective cardiomyocyte maturation and impaired RAC1 activation in mutant hearts. These results support an infolding and RA-dependent fusion model of septal morphogenesis, providing new insights into ventricular development and the origins of CHD.