title: Fgfr2b mediated epithelial-mesenchymal interactions coordinate tooth morphogenesis and dental trigeminal axon patterning.
abstract: Dental trigeminal nerve fiber growth and patterning are strictly integrated with tooth morphogenesis, but it is still unknown, how these two developmental processes are coordinated. Here we show that targeted inactivation of the dental epithelium expressed Fgfr2b results in cessation of the mouse mandibular first molar development at the degenerated cap stage and the failure of the trigeminal molar nerve to establish the lingual branch at E13.5 stage while the buccal branch develops properly. This axon patterning defect correlates to the histological absence of the mesenchymal dental follicle and adjacent Semaphorin3A-free dental follicle target field as well as appearance of ectopic Sema3A expression domain in the lingual side of the epithelial bud. Although the mesenchymal ligands for Fgfr2b, Fgf3 and -10 were present in the Fgfr2b(-/)(-) dental mesenchyme, mutant dental epithelium showed dramatically reduced proliferation and the lack of Fgf3. Tgfbeta1, which controls Sema3A was absent from the Fgfr2b(-/-) tooth germ, and Sema3A was specifically downregulated in the dental mesenchyme at the bud and cap stage. In addition, the epithelial primary enamel knot signaling center although being molecularly present neither was histologically detectable nor expressed Bmp4 and Fgf3 as well as Fgf4, which is essential for tooth morphogenesis and stimulates mesenchymal Fgf3 and Tgfbeta1. Fgf4 beads rescued Tgfbeta1 in the Fgfr2b(-/-) dental mesenchyme explants and Tgfbeta1 induced de novo Sema3A expression in the dental mesenchyme. Collectively these results demonstrate that epithelial Fgfr2b controls tooth morphogenesis and dental axon patterning, and suggests that Fgfr2b, by mediating local epithelial-mesenchymal interactions, integrates these two distinct developmental processes during odontogenesis.
authors.affiliation: Section of Anatomy and Cell Biology, Department of Biomedicine, Medical Faculty, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. Paivi.Kettunen@biomed.uib.no
authors.forename: Päivi
authors.initials: P
authors.lastname: Kettunen
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Tomasz
authors.initials: T
authors.lastname: Furmanek
authors.forename: Inger Hals
authors.initials: IH
authors.lastname: Kvinnsland
authors.forename: Clive
authors.initials: C
authors.lastname: Dickson
authors.forename: Irma
authors.initials: I
authors.lastname: Thesleff
authors.forename: Keijo
authors.initials: K
authors.lastname: Luukko
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism*; D019521:Body Patterning; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008963:Molar / Q000166:cytology / Q000196:embryology; D009414:Nerve Growth Factors / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000172:deficiency / Q000378:metabolism*; D040121:Semaphorin-3A / Q000378:metabolism; D014070:Tooth / Q000166:cytology / Q000196:embryology*; D014083:Tooth Germ / Q000166:cytology / Q000196:embryology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000196:embryology*
chemical_list: D009414:Nerve Growth Factors; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D053773:Transforming Growth Factor beta1; D051497:Receptor, Fibroblast Growth Factor, Type 2