title: Lunatic fringe, FGF, and BMP regulate the Notch pathway during epithelial morphogenesis of teeth.
abstract: Teeth develop as epithelial appendages, and their morphogenesis is regulated by epithelial-mesenchymal interactions and conserved signaling pathways common to many developmental processes. A key event during tooth morphogenesis is the transition from bud to cap stage when the epithelial bud is divided into specific compartments distinguished by morphology as well as gene expression patterns. The enamel knot, a signaling center, forms and regulates the shape and size of the tooth. Mesenchymal signals are necessary for epithelial patterning and for the formation and maintenance of the epithelial compartments. We studied the expression of Notch pathway molecules during the bud-to-cap stage transition of the developing mouse tooth. Lunatic fringe expression was restricted to the epithelium, where it formed a boundary flanking the enamel knot. The Lunatic fringe expression domains overlapped only partly with the expression of Notch1 and Notch2, which were coexpressed with Hes1. We examined the regulation of Lunatic fringe and Hes1 in cultured explants of dental epithelium. The expression of Lunatic fringe and Hes1 depended on mesenchymal signals and both were positively regulated by FGF-10. BMP-4 antagonized the stimulatory effect of FGF-10 on Lunatic fringe expression but had a synergistic effect with FGF-10 on Hes1 expression. Recombinant Lunatic fringe protein induced Hes1 expression in the dental epithelium, suggesting that Lunatic fringe can act also extracellularly. Lunatic fringe mutant mice did not reveal tooth abnormalities, and no changes were observed in the expression patterns of other Fringe genes. We conclude that Lunatic fringe may play a role in boundary formation of the enamel knot and that Notch-signaling in the dental epithelium is regulated by mesenchymal FGFs and BMP.
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki, Helsinki FIN-00014, Finland.
authors.forename: Tuija
authors.initials: T
authors.lastname: Mustonen
authors.forename: Mark
authors.initials: M
authors.lastname: Tümmers
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Mikami
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Itoh
authors.forename: Niang
authors.initials: N
authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Irma
authors.initials: I
authors.lastname: Thesleff
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051880:Receptors, Notch; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014070:Tooth / Q000196:embryology* / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors; D016695:Glycosyltransferases; D018398:Homeodomain Proteins; D008024:Ligands; D008565:Membrane Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; C496464:Fgf10 protein, mouse; C496465:Fgf10 protein, rat; C489734:Hes1 protein, mouse; C489735:Hes1 protein, rat; C489685:Hes5 protein, mouse; C489686:Hes5 protein, rat; C112971:fibroblast growth factor 14; C077478:HES5 protein, human; C498393:LFNG protein, human; C498392:Lfng protein, mouse; C498391:Lfng protein, rat