Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Abstract

Rationale The Dorsal Mesenchymal Protrusion (DMP) is a prong of mesenchyme derived from the Second Heart Field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular septal defect (AVSD). Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated. Objective To determine the role of BMP signaling in DMP development. Methods and Results Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AVSDs. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/TGFβ signaling was not significantly altered in the AV cushions of SHF-Alk3 mutants. Conclusions BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.

Heart Fields and Cardiac Morphogenesis

“…Notch and noncanonical WNT signaling also regulate differentiation during second heart field deployment (High et al 2009;Rochais et al 2009). At the venous pole of the heart, WNT, Hedgehog, and BMP signaling have been shown to play important roles in regulating progenitor cell deployment and atrial septation (Xie et al 2012;Briggs et al 2013).…”

“…These anomalies result from failure of development of a structure called the dorsal mesenchymal protrusion that plays a critical role in atrial and atrioventricular septation. The dorsal mesenchymal protrusion is derived from Isl1 and Tbx5 expressing progenitor cells in the posterior second heart field and requires Hedgehog and BMP signaling for its correct development (Snarr et al 2007;Hoffmann et al 2009;Briggs et al 2013). It is important to note that perturbations of the final stages of heart tube extension have a greater likelihood of being encountered in human congenital heart defects than more severe earlier perturbations.…”

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

“…For example, genetic inducible fate mapping (GIFM) has shown that the entire atrial septum, including the DMP, derives from the SHF (32). Furthermore, the molecular requirement for the Hedgehog (Hh) and BMP signaling pathways and the Tbx5 cardiogenic transcription factor for AV septation reside in the SHF (32)(33)(34)(35)(36)(37)(38). These observations lay the groundwork for investigating the molecular pathways required for atrial septum formation in SHF cardiac progenitor cells.…”

The Short Stature Homeobox 2 (Shox2)-bone Morphogenetic Protein (BMP) Pathway Regulates Dorsal Mesenchymal Protrusion Development and Its Temporary Function as a Pacemaker during Cardiogenesis

“…The AV junction that lies at the merging point of cardiac chambers is critically involved in both septum and CCS developmental processes (2). It comprises the dorsally positioned second heart field-derived dorsal mesenchymal protrusion (DMP) that gives rise to the future vestibular spine (2) and ventrally positioned endocardial cushion tissue as well as AV canal-derived myocardium including AVN precursors (3,4), The outgrowth and fusion of DMP and endocardial cushion tissue are essential for proper formation of AV septation (2,5). During cardiogenesis in mice, in the initial simple heart tube at embryonic day 8.5 (E8.5), the ring-like AV canal, which connects single atrium and ventricle, functions to generate the delay between the atrial and ventricular contraction (6).…”