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

Abstract

The morphogenesis and cell differentiation in developing teeth is governed by interactions between the oral epithelium and neural crest‐derived ectomesenchyme. The fibroblast growth factors FGF‐4, ‐8, and ‐9 have been implicated as epithelial signals regulating mesenchymal gene expression and cell proliferation during tooth initiation and later during epithelial folding morphogenesis and the establishment of tooth shape. To further evaluate the roles of FGFs in tooth development, we analyzed the roles of FGF‐3, FGF‐7, and FGF‐10 in developing mouse teeth. In situ hybridization analysis showed developmentally regulated expression during tooth formation for Fgf‐3 and Fgf‐10 that was mainly restricted to the dental papilla mesenchymal cells. Fgf‐7 transcripts were restricted to the developing bone surrounding the developing tooth germ. Fgf‐10 expression was observed in the presumptive dental epithelium and mesenchyme during tooth initiation, whereas Fgf‐3 expression 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 dental 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 putative 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. Down‐regulation of Fgf‐3 and Fgf‐10 expression in postmitotic odontoblasts correlated with the terminal differentiation of the odontoblasts 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 and Fgf‐10 in the dental mesenchyme was dependent on dental epithelium and that epithelially expressed FGFs, FGF‐4 and ‐8 induced Fgf‐3 but not Fgf‐10 expression in the isolated dental mesenchyme. Beads soaked in Shh, BMP‐2, and TGF‐β1 protein did not induce either Fgf‐3 or Fgf‐10 expression. Cells expressing Wnt‐6 did not induce Fgf‐10 expression. Furthermore, FGF‐10 protein stimulated cell proliferation in the dental epithelium but not in the mesenchyme. These results suggest that FGF‐3 and FGF‐10 have redundant functions as mesenchymal signals regulating epithelial morphogenesis of the tooth and that their expressions appear to be differentially regulated. In addition, FGF‐3 may participate in signaling functions of the primary enamel knot. The dynamic expression patterns of different Fgfs in dental epithelium and mesenchyme and their interactions suggest existence of regulatory signaling cascades between epithelial and mesenchymal FGFs during tooth development. © 2000 Wiley‐Liss, Inc.

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate

“…This thickened epithelium signals back to the underlying mesenchyme to direct growth and patterning. We have previously shown that in both limbs and teeth, Fgf10/Fgfr2b signaling plays important roles in initial budding and in maintaining growth (24,26). Here we provide evidence that Fgf10 signals from the palatal mesenchyme to its receptor in the palatal epithelium and that signals pass back to the mesenchyme.…”

“…Preparation of Fgfr2b, Fgf3, Fgf7, Fgf10, Ptc1, and Shh 35 S-UTP-labeled riboprobes, in situ hybridization, and image analysis have all been described previously (5,26,(48)(49)(50). Antisense Smo probe (a kind gift from M.T.…”

Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages

“…Furthermore, Wnt signaling was shown to be required in the molar mesenchyme for the bud to cap stage transition and primary enamel knot formation (Chen et al 2009). The signals induced in the mesenchyme by epithelial Fgfs and acting reciprocally to the epithelium include Activin, Fgf3, and Fgf10 (Ferguson et al 1998;Kettunen et al 2000). These signals regulate the subsequent epithelial morphogenesis and the enamel knot formation (Fig.…”

Revisiting the supernumerary: the epidemiological and molecular basis of extra teeth

“…34,35 Importantly, there is also evidence that signalling from Fgf3 and Fgf10 in mesenchyme of the tooth bud is also required for Shh expression in the primary enamel knot epithelium. 36,37 Sprouty (Spry) genes encode a small group of intracellular FGF antagonists which are produced in response to FGF signalling and therefore modulate transduction in target cells. 38 Among these genes, Spry2 and Spry4 are expressed in epithelium and mesenchyme of the developing tooth, respectively, and a loss-offunction associated with either gene results in the formation of extra teeth within the diastema region of the mouse dentition, predominantly affecting the mandible.…”