The Dorsal Mesenchymal Protrusion and the Pathogenesis of Atrioventricular Septal Defects

Abstract

Congenital heart malformations are the most common type of defects found at birth. About 1% of infants are born with one or more heart defect on a yearly basis. Congenital Heart Disease (CHD) causes more deaths in the first year of life than any other congenital abnormality, and each year, nearly twice as many children die in the United States from CHD as from all forms of childhood cancers combined. Atrioventricular septal defects (AVSD) are congenital heart malformations affecting approximately 1 in 2000 live births. Babies born with an AVSD often require surgical intervention shortly after birth. However, even after successful surgery, these individuals typically have to deal with lifelong complications with the most common being a leaky mitral valve. In recent years the understanding of the molecular etiology and morphological mechanisms associated with the pathogenesis of AVSDs has significantly changed. Specifically, these studies have linked abnormal development of the Dorsal Mesenchymal Protrusion (DMP), a Second Heart Field-derived structure, to the development of this congenital defect. In this review we will be discuss some of the latest insights into the role of the DMP in the normal formation of the atrioventricular septal complex and in the pathogenesis of AVSDs.

Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion

“…Posteriorly, atrioventricular septation requires a coordinated organization of the primary atrial septum (PAS), atrioventricular cushion (AVC), and dorsal mesenchymal protrusion (DMP) (Briggs et al, 2012; Burns et al, 2016). Starting around E9.5-E10.0, the SHF-derived DMP expands on the right side of the pulmonary ridges and protrudes into the atrial lumen in wild-type mouse embryos (Fig.…”

“…To further investigate the mechanisms by which WNT11 might be required to drive proliferation of DMP, we examined potential interactions between WNT11 and several other pathways previously shown to be required for proliferation of the DMP, including sonic hedgehog, canonical WNT, and PITX2 pathways (Burns et al, 2016). Ablation of the POU-homeodomain transcription factor Pitx2 leads to OFT and atrial septation defects (Kitamura et al, 1999).…”

“…Subsequent septation of the aorta and pulmonary artery is additionally dependent on mesenchymal cells from the cardiac neural crest and endocardium-derived outflow cushions (Anderson et al, 2016; Evans et al, 2010; Lin et al, 2012). Atrioventricular septation into left and right components is a highly complex event requiring input from second heart field-derived atrial myocardium, the endocardium-derived mesenchymal cap (MC) of the primary atrial septum, endocardium-derived atrioventricular cushions (AVC), and the dorsal mesenchymal protrusion (DMP) (Briggs et al, 2012; Burns et al, 2016; Kim et al, 2001; Lin et al, 2012). The DMP is a pSHF-derived mesenchymal tissue that starts to protrude from the dorsal mesocardium into the atrial lumen around embryonic day 10 (E10) in the mouse (Anderson et al, 2014; Mommersteeg et al, 2006).…”

A Novel Mouse Model for Cilia‐Associated Cardiovascular Anomalies with a High Penetrance of Total Anomalous Pulmonary Venous Return

“…The abnormal connections of the pulmonary veins at the venous pole as observed in the col3.6-cre;Ift88 Δ/fl mouse resemble a cyanotic congenital heart defect in the human known as total anomalous pulmonary venous return (TAPVR). (Snarr et al, 2008;Burns et al, 2016). During normal development, the DMP penetrates the dorsal mesocardium between ED9.5 and ED10.5 to the right of the primitive pulmonary vein (pPuV) which is initially a midline structure (Briggs et al, 2012).…”

“…The location of the connection of the primitive pulmonary vein(s) to the common atrium is not well-defined. DM, dorsal mesocardium; LV, left ventricle; pPuV, primitive pulmonary vein; RA, right atrium et al, 2008;Briggs et al, 2012;Burns et al, 2016). As the DMP, using the dorsal mesocardium as its "portal of entry", wedges itself in between the primitive pulmonary vein (PuV) and the right-sided mesocardial reflection into the common atrium, the common orifice of the developing pulmonary vein shifts to the left.…”