The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion

Abstract

Partitioning of the four-chambered heart requires the proper formation, interaction and fusion of several mesenchymal tissues derived from different precursor populations that together form the atrioventricular mesenchymal complex. This includes the major endocardial cushions and the mesenchymal cap of the septum primum, which are of endocardial origin, and the dorsal mesenchymal protrusion (DMP), which is derived from the Second Heart Field. Failure of these structures to develop and/or fully mature results in atrial septal defects (ASDs) and atrioventricular septal defects (AVSD). AVSDs are congenital malformations in which the atria are permitted to communicate due to defective septation between the inferior margin of the septum primum and the atrial surface of the common atrioventricular valve. The clinical presentation of AVSDs is variable and depends on both the size and/or type of defect; less severe defects may be asymptomatic while the most severe defect, if untreated, results in infantile heart failure. For many years, maldevelopment of the endocardial cushions was thought to be the sole etiology of AVSDs. More recent work, however, has demonstrated that perturbation of DMP development also results in AVSD. Here, we discuss in detail the formation of the DMP, its contribution to cardiac septation and describe the morphological features as well as potential etiologies of ASDs and AVSDs.

Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation

“…The implication of Tbx5 and Osr1 interaction in the SHF for atrioventricular septation buttresses our previous implication of Tbx5 and a growing body of literature indicating that SHF defects can cause AVSDs [10, 11, 23, 49-51]. In the present report, we showed an increased incidence of primum AVSDs in Tbx5 and Osr1 compound heterozygotes (Figure 3), a result that confirmed the interaction between Tbx5 and Osr1 in the pSHF for atrial septation.…”

Reply to Kelder et al.: Does the Dorsal Mesenchymal Protrusion Act as a Temporary Pacemaker during Heart Development?

“…In response to their comments, our replies are as follows. The anatomical identity of the derivatives of dorsal mesenchymal protrusion (DMP) in our studies is in agreement with that described previously (2-5), which can be mapped by Mef2c-AHF-Cre (3,5), and was also shown to be overlapped with Shox2 expression (2). We also found that Shox2 is co-expressed with Hcn4, Nkx2-5, and cTnT in the DMP derivatives at E11.0 ( Fig.…”

Probing chromatin landscape reveals roles of endocardial TBX20 in septation

“…AP1 proteins regulate a variety of processes including cell proliferation and survival, differentiation, growth, migration, and transformation. Intriguingly, conditional deletion of the AP1 family member Jun using Tie2-Cre leads to DORV, VSDs, and valve defects (54), suggesting that perhaps JUN cooperates with TBX20 in endocardial lineages to effect ture required for proper atrioventricular septation (13,53). Notably, this defect was not observed in our analysis of Nfatc1-Cre Tbx20 fl/fl mutants.…”