title: TNF signaling via the ligand-receptor pair ectodysplasin and edar controls the function of epithelial signaling centers and is regulated by Wnt and activin during tooth organogenesis.
abstract: Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and   glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a   novel TNF family ligand, ectodysplasin, and TNF receptor, edar. This has indicated a developmental   regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of   ectodysplasin (encoded by the Tabby gene) and edar (encoded by the downless gene) during mouse   tooth morphogenesis showed that they are expressed in complementary patterns exclusively in   ectodermal tissue layer. Edar was expressed reiteratively in signaling centers regulating key steps in   morphogenesis. The analysis of the effects of eight signaling molecules in the TGFbeta, FGF, Hh, Wnt, and   EGF families in tooth explant cultures revealed that the expression of edar was induced by activinbetaA,   whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was   downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that   signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling   centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of   ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin   signaling were identified among several genes expressed in the signaling centers. We conclude that   ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function,   but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with   epithelial-mesenchymal interactions and with other signaling pathways regulating organogenesis. We   suggest that activin signaling from mesenchyme induces the expression of the TNF receptor edar in the   epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby   ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki, 00014,   Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Laurikkala
authors.forename: M
authors.initials: M
authors.lastname: Mikkola
authors.forename: T
authors.initials: T
authors.lastname: Mustonen
authors.forename: T
authors.initials: T
authors.lastname: Aberg
authors.forename: P
authors.initials: P
authors.lastname: Koppinen
authors.forename: J
authors.initials: J
authors.lastname: Pispa
authors.forename: P
authors.initials: P
authors.lastname: Nieminen
authors.forename: J
authors.initials: J
authors.lastname: Galceran
authors.forename: R
authors.initials: R
authors.lastname: Grosschedl
authors.forename: I
authors.initials: I
authors.lastname: Thesleff
mesh_terms: D028341:Activins; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D003433:Crosses, Genetic; D053331:Ectodysplasins; D004815:Epidermal Growth Factor / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D007265:Inhibins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000502:physiology; D008963:Molar / Q000196:embryology*; D009805:Odontogenesis / Q000502:physiology*; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D053331:Ectodysplasins; C506019:Eda protein, mouse; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D008565:Membrane Proteins; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish; D028341:Activins; D007265:Inhibins; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor