Fgfr2b mediated epithelial-mesenchymal interactions coordinate tooth morphogenesis and dental trigeminal axon patterning

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 Fgfr2t results in cessation of the mouse mandibular first molar development at the degenerated cap stage and the failure of the trigeminal molarnerve to establish the lingual branch at E 13.5 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 appear,,, ance of ectopic Sema3A expression domain in the lingual side of the epithelial bud. Although the mesenchymal ligands for Fgfr2b, Fgfr and -10 were present in the Fgfr2b(-/-) dental mesenchyme, mutant dental epithelium showed dramatically reduced proliferation and the lack of Fgf3. Tgf beta 1, which controls Sema3A was absent from the Fgfr2b(-/-) tooth germ, and Sema3A was specifically downregulated it the dental mesenchyme at the bud and cap stage. In addition, the epithelial primary enamel knot signaling center although being molec ularly present neither was histologically detectable nor expressed Bmp4 and Fg13 as well as Fgf4, which is essential for tooth morpho genesis and stimulates mesenchymal Fg13 and Tgf beta 1. Fgf4 beads rescued Tgf beta 1 in the Fgfr2b-1- dental mesenchyme explants and Tgf beta. 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, inte grates these two distinct developmental processes during odontogenesis. (c) 2007 Elsevier Ireland Ltd. All rights reserved.