Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart.
Developmental abnormalities in endocardial cushions frequently contribute to congenital heart malformations including septal and valvular defects. While compelling evidence has been presented to demonstrate that members of the TGF-beta superfamily are capable of inducing endothelial-to-mesenchymal transdifferentiation in the atrioventricular canal, and thus play a key role in formation of endocardial cushions, the detailed signaling mechanisms of this important developmental process, especially in vivo, are still poorly known. Several type I receptors (ALKs) for members of the TGF-beta superfamily are expressed in the myocardium and endocardium of the developing heart, including the atrioventricular canal. However, analysis of their functional role during mammalian development has been significantly complicated by the fact that deletion of the type I receptors in mouse embryos often leads to early embryonal lethality. Here, we used the Cre/loxP system for endothelial-specific deletion of the type I receptor Alk2 in mouse embryos. The endothelial-specific Alk2 mutant mice display defects in atrioventricular septa and valves, which result from a failure of endocardial cells to appropriately transdifferentiate into the mesenchyme in the AV canal. Endocardial cells deficient in Alk2 demonstrate decreased expression of Msx1 and Snail, and reduced phosphorylation of BMP and TGF-beta Smads. Moreover, we show that endocardial cells lacking Alk2 fail to delaminate from AV canal explants. Collectively, these results indicate that the BMP type I receptor ALK2 in endothelial cells plays a critical non-redundant role in early phases of endocardial cushion formation during cardiac morphogenesis.
Wang
Jikui
J
Developmental Biology, The Saban Research Institute of Children's Hospital Los Angeles, CA 90027, USA.
Sridurongrit
Somyoth
S
Dudas
Marek
M
Thomas
Penny
P
Nagy
Andre
A
Schneider
Michael D
MD
Epstein
Jonathan A
JA
Kaartinen
Vesa
V
D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D004694:Endocardial Cushion Defects / Q000196:embryology* / Q000235:genetics; D005318:Fetal Heart / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology
D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse