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Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs

¹ Division of Molecular Medicine and Genetics, Department of Internal Medicine, ² the Life Sciences Institute, ³ the Biomedical Research Core Facilities, ⁴ Department of Human Genetics, ⁵ Department of Pathology, and ⁶ Program in Cell and Molecular Biology, University of Michigan, Ann Arbor, MI 48109
⁷ Institute of Biomedicine/Anatomy, University of Helsinki, FIN-00014 Helsinki, Finland
⁸ Programa de Recerca en Cancer, Institut Municipal d'Investigació Mèdica Hospital del Mar Universitat Pompeu Fabra, 08003 Barcelona, Spain
⁹ Institute of Pathology, Technical University of Munich, D-81675 Munich, Germany
¹⁰ The Finsen Laboratory, Department 3735, Rigshospitalet, DK-2200 Copenhagen N, Denmark

Correspondence to Stephen J. Weiss: sjweiss{at}umich.edu

Epithelial–mesenchymal transition (EMT) is required for mesodermal differentiation during development. The zinc-finger transcription factor, Snail1, can trigger EMT and is sufficient to transcriptionally reprogram epithelial cells toward a mesenchymal phenotype during neoplasia and fibrosis. Whether Snail1 also regulates the behavior of terminally differentiated mesenchymal cells remains unexplored. Using a Snai1 conditional knockout model, we now identify Snail1 as a regulator of normal mesenchymal cell function. Snail1 expression in normal fibroblasts can be induced by agonists known to promote proliferation and invasion in vivo. When challenged within a tissue-like, three-dimensional extracellular matrix, Snail1-deficient fibroblasts exhibit global alterations in gene expression, which include defects in membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive activity. Snail1-deficient fibroblasts explanted atop the live chick chorioallantoic membrane lack tissue-invasive potential and fail to induce angiogenesis. These findings establish key functions for the EMT regulator Snail1 after terminal differentiation of mesenchymal cells.

© 2009 Rowe 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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This article has been cited by other articles:

• Lu, C., Li, X.-Y., Hu, Y., Rowe, R. G., Weiss, S. J. (2010). MT1-MMP controls human mesenchymal stem cell trafficking and differentiation. Blood 115: 221-229 [Abstract] [Full Text]  
• Ota, I., Li, X.-Y., Hu, Y., Weiss, S. J. (2009). Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc. Natl. Acad. Sci. USA 106: 20318-20323 [Abstract] [Full Text]  
• Short, B. (2009). Fibroblasts invade at a Snail's pace. JCB 184: 339-339 [Full Text]  

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