{beta}-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse

doi:10.1083/jcb.200403050

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Published 2 August 2004. doi:10.1083/jcb.200403050
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JCB, Volume 166, Number 3, 359-367

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Article

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

Stefan Liebner¹, Anna Cattelino¹, Radiosa Gallini¹, Noemi Rudini¹, Monica Iurlaro¹^,3, Stefano Piccolo⁴, and Elisabetta Dejana¹^,2^,3

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-mesenchymaltransformation (EMT) and invade the underlying cardiac jelly.This process gives rise to the endocardial cushions from whichAV valves and part of the septum originate. In this paper weshow that in mouse embryos and in AV explants TGFßinduction of endocardial EMT is strongly inhibited in mice deficientfor endothelial ß-catenin, leading to a lack of heartcushion formation. Using a Wnt-signaling reporter mouse strain,we demonstrated in vivo and ex vivo that EMT in heart cushionis accompanied by activation of ß-catenin/TCF/Leftranscriptional activity. In cultured endothelial cells, TGFß2induces ${alpha}$ -smooth muscle actin ( ${alpha}$ SMA) expression. This processwas strongly reduced in ß-catenin null cells, althoughTGFß2 induced smad phosphorylation was unchanged.These data demonstrate an involvement of ß-catenin/TCF/Leftranscriptional activity in heart cushion formation, and suggestan interaction between TGFß and Wnt-signaling pathwaysin 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: ${alpha}$ SMA, ${alpha}$ -smooth muscle actin;AV, atrio-ventricular; dpc, d post coitum; EMT, epithelial-mesenchymaltransformation; KO, knockout; P-smad1/5, phospho-smad1/5; P-smad2,phospho-smad2; R-smad, receptor smad; WT, wild-type.

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