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¹ Department of Medical Biophysics, British Columbia Cancer Agency, Vancouver V5Z 1L3, Canada
² The Experimental Medicine Program and ³ The Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 1Z4, Canada
⁴ Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver V5Z 1L3, Canada
⁵ The Department of Medical Genetics, University of British Columbia, Vancouver V6T 1Z4, Canada

Correspondence to Aly Karsan: akarsan{at}bccrc.ca

Snail family proteins are key regulators of epithelial-mesenchymal transition, but their role in endothelial-to-mesenchymal transition (EMT) is less well studied. We show that Slug, a Snail family member, is expressed by a subset of endothelial cells as well as mesenchymal cells of the atrioventricular canal and outflow tract during cardiac cushion morphogenesis. Slug deficiency results in impaired cellularization of the cardiac cushion at embryonic day (E)–9.5 but is compensated by increased Snail expression at E10.5, which restores cardiac cushion EMT. We further demonstrate that Slug, but not Snail, is directly up-regulated by Notch in endothelial cells and that Slug expression is required for Notch-mediated repression of the vascular endothelial cadherin promoter and for promoting migration of transformed endothelial cells. In contrast, transforming growth factor β (TGF-β) induces Snail but not Slug. Interestingly, activation of Notch in the context of TGF-β stimulation results in synergistic up-regulation of Snail in endothelial cells. Collectively, our data suggest that combined expression of Slug and Snail is required for EMT in cardiac cushion morphogenesis.

Abbreviations used in this paper: AV, atrioventricular; ChIP, chromatin immunoprecipitation; E, embryonic day; EMSA, electrophoretic mobility shift assay; EMT, endothelial-to-mesenchymal transformation; HMEC, human mammary epithelial cell; HUVEC, human umbilical vein epithelial cell; OFT, outflow tract; qRT-PCR, quantitative RT-PCR; shRNA, short hairpin RNA; TSS, transcriptional start site; VE-cadherin, vascular endothelial cadherin.

© 2008 Niessen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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