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.

Keywords: AVSD; DMP; atrioventricular septal defects; congenital heart defect; development; dorsal mesenchymal protrusion; etiology; pathogenesis.

Figure 1

Anatomy of the atrioventricular septation complex in a human four-chambered heart with normal anatomy and in hearts with AVSDs. (A) shows a properly septated heart with a complete atrial and ventricular septum; (B) depicts a heart with an incomplete AVSD; and in (C) a heart with a complete AVSD is shown. Note that when a primary atrial septal defect is observed, the muscular rim at the base of the atrial septum is missing. IVS = interventricular septum, pAS = primary atrial septum, pASD = primary atrial septal defect, LA = left atrium, LV = left ventricle, RA = right atrium, RV = right ventricle, VSD = ventricular septal defect.

Figure 2

Development of the Atrioventricular Cushions. During formation of the heart tube, extracellular matrix-rich cardiac jelly (yellow) first accumulates between the endocardium and myocardium (left). During looping additional accumulation and endoEMT at the dorsal and ventral aspect of the AV canal results in formation of the major AV cushions (middle). The lateral cushions (green) form around the time the major cushions are fusing to separate left and right AV canal (right). CJ = cardiac jelly, Endo = endocardium, Epi = epicardium, Myo = myocardium, iAVC = inferior AV cushion, sAVC = superior AV cushion, ll-AVC = left lateral AV cushion, rl-AVC = right lateral AV cushion.

Figure 3

The Dorsal Mesocardium and the development of the Dorsal Mesenchymal Protrusion. (A,B) show a section of the venous pole of a mouse heart at 9.5ED stained for the expression of Isl1 ((B) is an enlargement of boxed area in (A)). Isl1 expression (brown nuclei) can be seen in the second heart field located between the dorsal mesocardium and the foregut. (C) is a section in the same area of a different heart at the same stage labeled for the expression of the myocardial marker Myosin Heavy Chain (red) and the expression of pSMAD1,5,8 (green) showing active BMP signaling. Note that the developing pulmonary vein is located in the midline of the dorsal mesocardium at this stage. The sections in (D,E) show the developing DMP at 10.5ED. (D,E) ((E) is an enlargement of the boxed area in (D)) show the penetrating DMP stained for Isl1 (green). (F) shows the DMP in a sister section stained for the proliferation marker ki67 (green) demonstrating that whereas there is active proliferation in the SHF itself, the level of proliferation in the SHF cells at the leading edge of the DMP is very low.

Figure 4

Atrial septation. This cartoon depicts the developmental events responsible for the formation of the atrial septal complex (see text). The yellow box in the back of the heart represents the posterior Second Heart Field giving rise to the DMP which in turn develops into the base of the atrial septal complexand becomes muscularized to form the muscular rim (B–D). The asterisk in (A) marks the primary foramen (also known as ostium primum); the asterisk in (C) marks the secondary interatrial foramen (also known as ostium secundum), which forms as a result of perforations in the upper part of the primary atrial septum (see (B)). DMP = dorsal mesenchymal protrusion, pf = primary foramen, FO = foramen ovale, LA = left atrium, LV = left ventricle, PAS = primary atrial septum, RA = right atrium, RV = right ventricle, “rim” = myocardial rim, sAS = secondary atrial septum.

Figure 5

Atrioventricular septal defect in Mef2C-AHF-Cre;Alk3^fl/fl mouse at ED13.5 Histological analysis of control (A) and SHF-specific Alk3 knockout (B) mouse embryos at ED13.5 shows that while the atrioventricular valvuloseptal complex is complete in the control specimen (A) the deletion of Alk3 from the SHF has resulted in an incomplete AVSD in the SHF-specific Alk3 knockout embryo (B). AVSD = atrioventricular septal defect, LA = left atrium, LV = left ventricle, RA = right atrium, RV = right ventricle.

Figure 6

Atrioventricular septal defect in Mef2C-AHF-Cre;Smo^fl/fl mouse at ED15.5. This figure shows a control (A) and SHF-specific Smo knockout (B) mouse embryo at ED15.5. The image in (A) demonstrates normal anatomy of the atrioventricular septal complex, whereas the conditional knockout embryo in (B) is characterized by an incomplete AVSD. Note also that the dorsal aorta in (A) is located in its normal position to the left of the esophagus and the embryonic midline while in (B) the dorsal aorta is located to the right of the esophagus. Ao = dorsal aorta, AVSD = atrioventricular septal defect, Eso = esophagus, pAS = primary atrial septum.

Figure 7

Model of a posterior SHF-DMP precursor cell. This simplified cartoon of a DMP precursor cell with a protruding primary cilium shows pathways and factors known to be involved in pSHF/DMP-dependent atrioventricular septation.