title: FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice.
abstract: Lymphoid enhancer factor (LEF1), a nuclear mediator of Wnt signaling, is required for the formation of organs that depend on inductive interactions between epithelial and mesenchymal tissues. In previous tissue recombination experiments with normal and Lef1(-/-) tooth germs, we found that the effect of LEF1 expression in the epithelium is tissue nonautonomous and transferred to the subjacent mesenchyme. Here we examine the molecular basis for LEF1 function and find that the epithelium of the developmentally arrested Lef1(-/-) tooth rudiments fails to express Fgf4, Shh, and Bmp4, but not Wnt10a. We identify the Fgf4 gene as a direct transcriptional target for LEF1 and show that beads soaked with recombinant FGF4 protein can fully overcome the developmental arrest of Lef1(-/-) tooth germs. In addition, we find that FGF4 beads induce rapidly the expression of Fgf3 in dental mesenchyme and that both epithelial and mesenchymal FGF proteins induce the delayed expression of Shh in the epithelium. Taken together, these data indicate that a single target of LEF1 can account for the function of LEF1 in tooth development and for a relay of a Wnt signal reception to a cascade of FGF signaling activities, allowing for a sequential and reciprocal communication between epithelium and mesenchyme.
authors.affiliation: Institute of Molecular Biology, Austrian Academy of Sciences, 5020 Salzburg, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kratochwil
authors.forename: Juan
authors.initials: J
authors.lastname: Galceran
authors.forename: Sabine
authors.initials: S
authors.lastname: Tontsch
authors.forename: Wera
authors.initials: W
authors.lastname: Roth
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004627:Embryonic Induction; D004847:Epithelial Cells / Q000502:physiology; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009805:Odontogenesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014070:Tooth / Q000196:embryology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D053823:Hedgehog Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C525813:bmp4 protein, zebrafish; D005346:Fibroblast Growth Factors