title: The EDA gene is a target of, but does not regulate Wnt signaling.
abstract: Lesions in the anhidrotic ectodermal dysplasia (EDA) gene cause the recessive human genetic disorder X-linked anhidrotic ectodermal dysplasia, which is characterized by the poor development of ectoderm-derived structures. Ectodysplasin-A, the protein encoded by the EDA gene, is a member of the tumor necrosis factor ligand superfamily that forms a collagen triple helix, suggesting functions in signal transduction and cell adhesion. In an effort to elucidate the function of EDA in pathways regulating ectodermal development, we have analyzed promoter elements of the gene. We show here that a binding site for the lymphocyte enhancer factor 1 (Lef-1) transcription factor is active. In electrophoretic mobility shift assays, Lef-1 specifically bound to its site in the EDA promoter. Over-expression of both Lef-1 and beta-catenin significantly increased EDA transcription in co-transfection studies. In addition, indirect stabilization of endogenous beta-catenin stimulated EDA transcription 4- to 13-fold. This is the first direct evidence of a relationship between EDA and the Wnt pathway. We have also investigated whether EDA might function in a feedback loop to modulate Wnt signaling. Over-expression of EDA neither stimulated basal transcription of Wnt-dependent genes, nor inhibited Wnt-dependent activation of transcription. Taken together, our results demonstrate that Wnt signaling does control EDA gene expression, but ectodysplasin-A does not feedback on the Wnt pathway.
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Triad Technology Center, Suite 4000, 333 Cassell Drive, Baltimore, MD 21224, USA. durmowiczm@grc.nia.nih.gov
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Durmowicz
authors.forename: Chang Yi
authors.initials: CY
authors.lastname: Cui
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053331:Ectodysplasins; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3; D006367:HeLa Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: D004268:DNA-Binding Proteins; C506018:EDA protein, human; D053331:Ectodysplasins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3