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Published 22 December 2003. doi:10.1083/jcb.200306024
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© The Rockefeller University Press, 0021-9525/2003/12/1291 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1291-1301

Article

TGFß3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development



Ali Nawshad and Elizabeth D. Hay

Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Address correspondence to Dr. Elizabeth D. Hay, Dept. of Cell Biology, Harvard Medical School, 220 Longwood Ave., B-1, Room 342, Boston, MA 02115-6092. Tel.: (617) 432-1651. Fax: (617) 432-0407. email: ehay{at}hms.harvard.edu

Epithelial mesenchymal transformation (EMT) of the medial edge epithelial (MEE) seam creates palatal confluence. This work aims to elucidate the molecular mechanisms by which TGFß3 brings about palatal seam EMT. We collected mRNA for PCR analysis from individual transforming MEE cells by laser microdissection techniques and demonstrated that TGFß3 stimulates lymphoid-enhancing factor 1 (LEF1) mRNA synthesis in MEE cells. We show with antisense ß-catenin oligonucleotides that up-regulated LEF1 is not activated by ß-catenin in palate EMT. We ruled out other TGFß3 targets, such as RhoA and MEK1/2 pathways, and we present evidence using dominant-negative Smad4 and dominant-negative LEF1 showing that TGFß3 uses Smads both to up-regulate synthesis of LEF1 and to activate LEF1 transcription during induction of palatal EMT. When phospho-Smad2 and Smad4 are present in the nucleus, LEF1 is activated without ß-catenin. Our paper is the first to show that the Smad2,4/LEF1 complex replaces ß-catenin/LEF1 during activation of EMT in vivo by TGFß3.

Key Words: LEF1 transcription; Smad2; palate confluence; ß-catenin; Smad pathways

Abbreviations used in this paper: AS, antisense; C3, Clostridium botulinum C3; DN, dominant negative; EMT, epithelial mesenchymal transformation; LCM, laser capture microdissection; LEF1, lymphoid-enhancing factor 1; MEE, medial edge epithelium.


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