TGFβ3 Inhibits E-Cadherin Gene Expression in Palate Medial-Edge Epithelial Cells Through a Smad2-Smad4- LEF1 Transcription Complex

Authors

• Ali Nawshad, University of Nebraska - Lincoln
• Damian Medici, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
• Chang-Chih Liu, University of Nebraska - Lincoln
• Elizabeth D. Hay, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA

Document Type

Article

Date of this Version

2007

Comments

Published in Journal of Cell Science 120, 1646-1653. Published by The Company of Biologists 2007. Used by permission.

Abstract

Dissociation of medial-edge epithelium (MEE) during palate development is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFβ3 upon adherence of opposing palatal shelves, because loss of E-cadherin causes the MEE seam to break into small epithelial islands. To investigate the molecular mechanisms that cause this E-cadherin loss, we isolated and cultured murine embryonic primary MEE cells from adhered or non-adhered palates. Here, we provide the first evidence that lymphoid enhancer factor 1 (LEF1), when functionally activated by phosphorylated Smad2 (Smad2- P) and Smad4 (rather than β-catenin), binds with the promoter of the E-cadherin gene to repress its transcription in response to TGFβ3 signaling. Furthermore, we found that TGFβ3 signaling stimulates epithelial-mesenchymal transformation (EMT) and cell migration in these cells. LEF1 and Smad4 were found to be necessary for up-regulation of the mesenchymal markers vimentin and fibronectin, independently of β- catenin. We proved that TGFβ3 signaling induces EMT in MEE cells by forming activated transcription complexes of Smad2-P, Smad4 and LEF1 that directly inhibit Ecadherin gene expression.