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A more recent version of this article appeared on August 1, 2007
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Submitted on September 29, 2006
Revised on April 11, 2007
Accepted on May 4, 2007
*Centre for Molecular Medicine, Faculty of Medical and Human Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Immunology Group and Cancer Research UK Stem Cell Biology Group, Paterson Institute for Cancer Research, University of Manchester, Christie Hospital National Health Service Trust, Manchester M20 4BX, United Kingdom; Materials Science Centre, The University of Manchester, Manchester M1 7HS, United Kingdom; ||Department of Molecular Embryology, Max-Planck Institute of Immunobiology, D-79108 Freiburg, Germany
Monitoring Editor: Marianne Bronner-Fraser
Epithelial-mesenchymal transition (EMT) events occur during embryonic development and are important for the metastatic spread of epithelial tumors. We show here that spontaneous differentiation of mouse ES cells is associated with an E- to N-cadherin switch, upregulation of E-cadherin repressor molecules (Snail and Slug proteins), gelatinase activity (MMP-2 and MMP-9) and increased cellular motility, all characteristic EMT events. The 5T4 oncofoetal antigen, previously shown to be associated with very early ES cell differentiation and altered motility, is also a part of this coordinated process. E-cadherin, N-cadherin and 5T4 proteins are independently regulated during ES cell differentiation and are not required for induction of EMT-associated transcripts and proteins, as judged from the study of the respective knockout ES cells. Further, abrogation of E-cadherin mediated cell-cell contact in undifferentiated ES cells using neutralizing antibody results in a reversible mesenchymal phenotype and actin cytoskeleton rearrangement which is concomitant with translocation of the 5T4 antigen from the cytoplasm to the cell surface in an energy-dependent manner. E-cadherin null ES cells are constitutively cell surface 5T4 positive and while forced expression of E-cadherin cDNA in these cells is sufficient to restore cell-cell contact, cell surface expression of 5T4 antigen is unchanged. 5T4 and N-cadherin knockout ES cells exhibit significantly decreased motility during EMT, demonstrating a functional role for these proteins in this process. We conclude that E-cadherin protein stabilizes cortical actin cyoskeletal arrangement in ES cells and this can prevent cell surface localization of the promigratory 5T4 antigen.
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