Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis

The morphogenesis and cell differentiation in developing teeth is governed by interactions between the oral epithelium and neural crest-derived ectome senchyme. The fibroblast growth factors FGF-4, -8, and -9 have been implica ted as epithelial signals regulating mesenchymal gene expression and cell p roliferation during tooth initiation and later during epithelial folding mo rphogenesis and the establishment of tooth shape, To further evaluate the r oles of FGFs in tooth development, we analyzed the roles of FGF-3, FGF-7, a nd FGF-10 in developing mouse teeth. In situ hybridization analysis showed developmentally regulated expression during tooth formation for Fgf-3 and F gf-10 that was mainly restricted to the dental papilla mesenchymal cells. F gf-7 transcripts were restricted to the developing bone surrounding the dev eloping tooth germ. Fgf-10 expression was observed in the presumptive denta l epithelium and mesenchyme during tooth initiation, whereas Fgf-3 expressi on appeared in the dental mesenchyme at the late bud stage. During the cap and bell stage, both Fgf-3 and Fgf-10 were intensely expressed in the denta l papilla mesenchymal cells both in incisors and molars. It is of interest that Fgf-3 expression was also observed in the primary enamel knot, a putat ive signaling center of the tooth, whereas no transcripts were seen in the secondary enamel knots that appear in the tips of future cusps of the bell stage tooth germs. Downregulation of Fgf-3 and Fgf-10 expression in postmit otic odontoblasts correlated with the terminal differentiation of the odont oblasts and the neighboring ameloblasts. In the incisors, mesenchymal cells of the cervical loop area showed partially overlapping expression patterns for all studied Fgfs, In vitro analyses showed that expression of Fgf-3 an d Fgf-10 in the dental mesenchyme was dependent on dental epithelium and th at epithelially expressed FGFs, FGF-4 and -8 induced Fgf-3 but not Fgf-10 e xpression in the isolated dental mesenchyme, Beads soaked in Shh, BMP-2, an d TGF-beta1 protein did not induce either Fgf-3 or Fgf-10 expression. Cells expressing Wnt-6 did not induce Fgf-10 expression. Furthermore, FGF-10 pro tein stimulated cell proliferation in the dental epithelium but not in the mesenchyme, These results suggest that FGF-3 and FGF-10 have redundant func tions as mesenchymal signals regulating epithelial morphogenesis of the too th and that their expressions appear to be differentially regulated. In add ition, FGF-3 may participate in signaling functions of the primary enamel k not. The dynamic expression patterns of different Fgfs in dental epithelium and mesenchyme and their interactions suggest existence of regulatory sign aling cascades between epithelial and mesenchymal FG;Fs during tooth develo pment. (C) 2000 Wiley-Liss, Inc.