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

¹ FIRC Institute of Molecular Oncology, University of Milan, 20139 Milan, Italy
² Mario Negri Institute for Pharmacological Research, University of Milan, 20139 Milan, Italy
³ Department of Biomolecular and Biotechnological Sciences, University of Milan, 20139 Milan, Italy
⁴ Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, 35100 Padua, Italy

Address correspondence to Elisabetta Dejana, FIRC Institute of Molecular Oncology, Via Adamello, 16-20139, Milan, Italy. Tel.: 39-02-574303-234. Fax: 39-02-574303-244. email: dejana{at}ifom-firc.it

During heart development endocardial cells within the atrio-ventricular (AV) region undergo TGFß-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 TGFß induction of endocardial EMT is strongly inhibited in mice deficient for endothelial ß-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 ß-catenin/TCF/Lef transcriptional activity. In cultured endothelial cells, TGFß2 induces -smooth muscle actin (SMA) expression. This process was strongly reduced in ß-catenin null cells, although TGFß2 induced smad phosphorylation was unchanged. These data demonstrate an involvement of ß-catenin/TCF/Lef transcriptional activity in heart cushion formation, and suggest an interaction between TGFß and Wnt-signaling pathways in the induction of endothelial-mesenchymal transformation.

Key Words: heart cushion formation; ß-catenin; endothelial cells; Wnt-signaling; transforming growth factor ß

Abbreviations used in this paper: SMA, -smooth muscle actin; AV, atrio-ventricular; dpc, d post coitum; EMT, epithelial-mesenchymal transformation; KO, knockout; P-smad1/5, phospho-smad1/5; P-smad2, phospho-smad2; R-smad, receptor smad; WT, wild-type.

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