β-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse

Abstract

During heart development endocardial cells within the atrio-ventricular (AV) region undergo TGFβ-dependent epithelial-mesenchymal transformation (EMT) and invade the underlying cardiac jelly. This process gives rise to the endocardial cushions from which AV valves and part of the septum originate. In this paper we show that in mouse embryos and in AV explants TGFβ induction of endocardial EMT is strongly inhibited in mice deficient for endothelial β-catenin, leading to a lack of heart cushion formation. Using a Wnt-signaling reporter mouse strain, we demonstrated in vivo and ex vivo that EMT in heart cushion is accompanied by activation of β-catenin/TCF/Lef transcriptional activity. In cultured endothelial cells, TGFβ2 induces α-smooth muscle actin (αSMA) expression. This process was strongly reduced in β-catenin null cells, although TGFβ2 induced smad phosphorylation was unchanged. These data demonstrate an involvement of β-catenin/TCF/Lef transcriptional activity in heart cushion formation, and suggest an interaction between TGFβ and Wnt-signaling pathways in the induction of endothelial-mesenchymal transformation.

Cardiac-specific haploinsufficiency of β-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction

“…Activation of β-catenin signaling, however, is required for in vitro cardiac myogenesis and differentiation [27]. More importantly, β-catenin knockout in the endothelium causes defects in cardiac septation and valve formation [9]. Our result reveal that homozygous deletion of β-catenin in cardiac myocytes is embryonically lethal, indicating that β-catenin is indispensable for late cardiac development.…”

“…Deletion of β-catenin disrupts axis formation. Conditional inactivation of β-catenin in endothelial cells also demonstrates that β-catenin plays a critical role during cardiac cushion development [9]. To investigate the direct role of β-catenin in cardiac development and hypertrophy, we specifically deleted β-catenin in cardiac myocytes by crossing loxP-floxed β-catenin mice [10] with transgenic mice expressing a Cre recombinase under the control of the α-myosin heavy chain promoter.…”

The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it

“…Heart development uses several TGF␤s in the chick and mouse embryo, including TGF␤2 and TGF␤3 (Runyan et al, 1992;Camenisch et al, 2002;Liebner et al, 2004;Timmerman et al, 2004). TGF␤2 influences the levels of Snail and VE-cadherin (see Takeichi, 1995, for review of other cadherins).…”

“…TGF␤2 influences the levels of Snail and VE-cadherin (see Takeichi, 1995, for review of other cadherins). There is overlap with Wnt pathways in the heart (Liebner et al, 2004), ␤-Catenin is required for EMT in mammalian heart cushion EMT, whereas the Notch gene seems to be required for endocardial EMT (Timmerman et al, 2004). Palates null for Notch are cleft, suggesting a role for Notch in palate EMT (Jiang et al, 1998), but the overall role of Notch in embryonic EMTs is not clear at this time.…”

“…Mouse palate uses Smad 2/4 to activate as well as synthesize LEF-1 (Nawshad et al, 2004). Mouse heart uses the Wnt EMT pathway (Liebner et al, 2004) and the avian heart uses both TGF␤2 and ␤3 as ligands for EMT in the formation of valve and septal mesenchymal cells. TGF␤2 and ␤3 have distinct roles to play in the chick and mouse heart as does slug, VE-cadherin, and Wnt (Camenisch et al, 2002).…”