Dgcr8 controls neural crest cells survival in cardiovascular development

DiGeorge syndrome (DGS), characterized genetically by a deletion within chromosome 22q11.2, is associated with a constellation of congenital heart defects. DiGeorge critical region 8 (Dgcr8), a gene that maps to the common deletion region of DGS, encodes a double stranded RNA-binding protein that is essential for miRNA biogenesis. To address the potential contribution of Dgcr8 insufficiency to cardiovascular development, we have inactivated Dgcr8 in cardiac neural crest cells (cNCCs). Dgcr8 mutants displayed a wide spectrum of malformations, including persistent truncus arteriosus (PTA) and ventricular septal defect (VSD). Interestingly, Dgcr8-null cNCCs that properly migrated into the cardiac outflow tract (OFT), proliferate normally and differentiate into vascular smooth muscle cells. However, loss of Dgcr8 causes a significant portion of the cNCCs to undergo apoptosis, causing a decrease in the pool of progenitors required for OFT remodeling. Our data uncover a new role of Dgcr8 in cardiovascular morphogenesis, plausibly as part of transmission mechanism for FGF-dependent survival cue for migrating cNCCs.

► DiGeorge critical region 8 (Dgcr8) is essential for miRNA biogenesis. ► Inactivation of Dgcr8 in cardiac neural crest cells (cNCCs) results in cardiovascular defects. ► Dgcr8-null cNCCs undergo apoptosis, decreasing the progenitor pool required for outflow tract remodeling. ► Dgcr8 maintains phosphoERK signaling, thus protecting from apoptosis.