title: Inhibition of Wnt signaling by exogenous Mfrzb1 protein affects molar tooth size.
abstract: Wnt extracellular signaling molecules have essential roles as regulators of cell proliferation, migration, differentiation, and in epithelial-mesenchymal interactions involved in tissue morphogenesis. Frizzled integral membrane proteins have been shown to function as receptors for Wnt signaling molecules. Vertebrates also produce secreted proteins related to Frizzled receptors, Frizzled-related proteins (FRPs), which contain the cysteine-rich domain of Frizzleds and appear to function as Wnt antagonists. Tooth development is regulated by a reciprocal series of epithelial-mesenchymal interactions, and many Wnt signaling pathway genes are expressed in the developing tooth at these sites. Here we report the expression of one FRP gene, Mfrzb1, in the rostral mesenchyme of the mandibular primordium. Using explant cultures, we show that expression of Mfrzb1 in the mandibular mesenchyme is under the control of signals derived from the overlying epithelium. Bead implantation experiments in vitro show that FGF8 induces Mfrzb1 expression, whereas BMP4 and SHH proteins have no effect. We studied the effect of ectopic MFrzb1 protein on the developing tooth germs by transplanting explants treated with Mfrzb1 protein into renal capsules, and found it to retard tooth development. This suggests that Wnt signaling is required early in tooth germ formation and that interference with signaling via addition of an antagonist results in retarded development and formation of smaller teeth.
authors.affiliation: Department of Craniofacial Development, GKT Dental Institute, Kings College, Guy's Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sarkar
authors.forename: P T
authors.initials: PT
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003545:Cysteine / Q000037:antagonists & inhibitors; D004627:Embryonic Induction; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008334:Mandible / Q000196:embryology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008648:Mesoderm / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008963:Molar / Q000033:anatomy & histology / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000494:pharmacology; D009805:Odontogenesis / Q000187:drug effects / Q000235:genetics; D009811:Odontometry; D009924:Organ Culture Techniques; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014083:Tooth Germ / Q000187:drug effects / Q000254:growth & development; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000099274:Frizzled-Related Proteins
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D003545:Cysteine; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000099274:Frizzled-Related Proteins; C525810:Bmp4 protein, mouse; C496457:Fgf8 protein, mouse; C525813:bmp4 protein, zebrafish