Formation of the Atrioventricular Septal Structures in the Normal Mouse

Abstract

—It is sometimes thought that formation of the atrioventricular septum is equated with fusion of the endocardial cushions and that failure of fusion can explain all deficiencies of atrioventricular septation. Clearly, this is simplistic, but the exact contribution of different primordia to atrioventricular septation is not well understood. To clarify this, we studied normal mouse embryos (days 10 to 15 of gestation), which were serially sectioned and examined by light microscopy. Another group of embryos was examined by scanning electron microscopy after microdissection. Our results show that development of the atrioventricular septal area is highly complex. Proper formation requires the following: remodeling of the inner heart curvature, rotation of the horns of the systemic venous sinus around the pulmonary portal, expansion of the right atrioventricular junction, formation of the muscular atrial and ventricular septa, bridging by the dextrodorsal outflow ridge and the superior endocardial cushion, fusion with the inferior margins of the venous valves, and formation of the mouth of the coronary sinus from the cranial muscular wall of the left sinus horn. Multiple primordia contribute to a central mesenchymal mass (the “septum intermedium”), including the mesenchyme on the leading edge of the primary atrial septum, the atrioventricular endocardial cushions, and the cap of mesenchyme on the spina vestibuli. Fusion of these components closes the ostium primum, completing atrial and atrioventricular septation. Additionally, the spina vestibuli has a mesodermal core, which contributes to the muscularization of the lower margin of the oval fossa. This contrasts with the formation of the upper rim, which occurs as a result of an infolding of the atrial wall itself.

Restoration of DSCR1 to disomy in the trisomy 16 mouse model of Down syndrome does not correct cardiac or craniofacial development anomalies

“…6A, asterisk), and continuity of the outflow tract and atrioventricular endocardial cushions ( Fig. 6A, arrowhead; Webb et al, 1998). In comparison, morphological abnormalities in cardiac looping and inner curvature remodeling previously reported in Ts16 embryos (Webb et al, 1996(Webb et al, , 1999 remain apparent in Ts16/Ds-DSCR1 embryos.…”

“…Normal cardiac looping and remodeling of the inner curvature of the heart are required for proper atrioventricular septation, and these processes are abnormal in Ts16 embryos (Webb et al, 1996(Webb et al, , 1998(Webb et al, , 1999. Morphology of the looping heart was examined by histology in E11.5 Ds16 and Ts16/Ds-DSCR1 embryos.…”

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

“…We observed defects that would be consistent with this hypothesis, including delayed fusion of cushions, and slight misalignment of muscular ventricular septum with the inferior atrioventricular cushion. Both these defects are known to contribute to defective ventricular septation (Webb et al, 1998). Alternatively, it is also formally possible that the high frequency of VSDs in these mutants may be a secondary consequence of cerebral haemorrhage leading to reduced blood flow that might, in turn, affect maturation of the heart.…”

A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development

“…With a majority of these defects involving abnormalities in valve and septal formation (Clark, 1987;Pierpont et al, 2000), great attention has been focused upon understanding the developmental processes of valvuloseptal morphogenesis (Odgers, 1939;Wenink and Gittenberger-de Groot, 1985;Lamers et al, 1995;Webb et al, 1998a;de Lange et al, 2004). An early event that appears to be critical in these events is the mesenchymalization of the endocardial cushions (Markwald et al, 1977).…”

“…While it is generally accepted that normal AV septation includes the complete fusion of the DMP and mesenchymal cap with the superior and inferior AV cushions, resulting in the formation of the AV mesenchymal complex and the closure of the primary atrial foramen (Webb et al, 1998a;Anderson et al, 1999), the origin of the DMP and the extent of its contribution to the AV mesenchymal complex have been controversial (Tasaka et al, 1996;Webb et al, 1998b;Wessels et al, 2000;Kim et al, 2001). Studies of the DMP in heart development have previously relied upon anatomical relationships and histological analyses of the DMP and surrounding tissues (Webb et al, 1998a,b;Anderson et al, 1999;Wessels et al, 2000;Kim et al, 2001;His, 1880).…”