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

Morphogenesis of the muscular ventricular septum in mouse hearts is controlled by retinoic acid signaling to the myocardium. The mammalian heart contains septa that separate systemic and pulmonary circulation, and these septa are sites of congenital heart defects (CHD). The muscular ventricular septum forms between left and right ventricular cardiomyocytes, which originate from the first and second heart fields.

However, the mechanisms behind the development of the ventricular septum are not well understood. This study demonstrates that the reception of retinoic acid (RA) signaling by the myocardium regulates the formation of the compact septal core. When a dominant negative RA receptor is activated in second heart field-derived myocardium during septal morphogenesis, it leads to a deep interventricular cleft and a bifid cardiac apex.

This phenotype is caused by ectopic trabecular contributions to a RA-independent septal primordium. The molecular analysis reveals defective cardiomyocyte maturation and impaired RAC1 activation in mutant hearts. These findings support an infolding and RA-dependent fusion model of septal morphogenesis, offering new insights into ventricular development and the origins of CHD.