Exploring the interface between the first and second heart fields: Implications for cardiac septation

Abstract

The embryonic heart elongates by progressive addition of second heart field (SHF) cardiac progenitor cells to the arterial and venous poles of the early heart tube, derived from the first heart field (FHF). The SHF gives rise to the right ventricle, outflow tract and part of the atrial myocardium. SHF-derived parts of the heart are hotspots of congenital heart defects (CHD) and perturbation of SHF deployment underlies a spectrum of CHD. These include atrial and ventricular septal defects that account for over 50% of CHD. Atrial septal structures originate in Tbx1 expressing cells in the posterior dorsal pericardial wall that activate the FHF regulator Tbx5 in response to retinoic acid (RA) signaling. Transient coexpression of Tbx1 and Tbx5 is followed by downregulation of the SHF program, and emergence of a sharp boundary between arterial and venous pole progenitor cells. A similar history of expression of both FHF and SHF regulators, followed by downregulation of the SHF program, demarcates boundary formation at the site of ventricular septation. Here we investigate the cellular and molecular mechanisms of ventricular septum morphogenesis. Using mouse genetics and a conditional dominant negative RA receptor, we show that RA signaling is also required at the heart field interface for morphogenesis of the muscular ventricular septum. Blocking RA signal reception in the SHF results in a bifid ventricular phenotype, identifying a novel RA-dependent zipper phase of ventricular septal morphogenesis. Additionally, blocking RA signal reception in the SHF results in conotruncal CHD. Together, our results point to the importance of RA signaling at the heart field interface for septal morphogenesis, providing new insights into the etiology of CHD.