FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1^−/− mice

Abstract

Lymphoid enhancer factor (LEF1), a nuclear mediator of Wnt signaling, is required for the formation of organs that depend on inductive interactions between epithelial and mesenchymal tissues. In previous tissue recombination experiments with normal and Lef1 −/− tooth germs, we found that the effect of LEF1 expression in the epithelium is tissue nonautonomous and transferred to the subjacent mesenchyme. Here we examine the molecular basis for LEF1 function and find that the epithelium of the developmentally arrested Lef1 −/− tooth rudiments fails to express Fgf4, Shh, and Bmp4, but not Wnt10a. We identify the Fgf4 gene as a direct transcriptional target for LEF1 and show that beads soaked with recombinant FGF4 protein can fully overcome the developmental arrest of Lef1 −/− tooth germs. In addition, we find that FGF4 beads induce rapidly the expression of Fgf3 in dental mesenchyme and that both epithelial and mesenchymal FGF proteins induce the delayed expression of Shh in the epithelium. Taken together, these data indicate that a single target of LEF1 can account for the function of LEF1 in tooth development and for a relay of a Wnt signal reception to a cascade of FGF signaling activities, allowing for a sequential and reciprocal communication between epithelium and mesenchyme.

Variability in dentofacial phenotypes in four families with WNT10A mutations

“…WNT genes are involved in hair-follicle morphogenesis, 27,28 skin and tooth embryogenesis [29][30][31] and several other developmental processes. 32 It also explains that in addition to TA, hypoplastic morphological dental features, including conical tooth shapes and microdontia, occur in the permanent teeth which did develop.…”

FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development

“…Some FGFs in addition to FGF20 also appear to be transcriptional targets for Wnt/b-catenin signaling. FGF4 has recently been reported to be a direct target of b-catenin (Kratochwil et al, 2002), and FGF9 RNA was reported to be present at elevated levels in OEAs with deregulated b-catenin (Schwartz et al, 2003). In Xenopus, expression of XFGF3 was shown to be regulated by the maternal b-catenin activity (Schohl and Fagotto, 2003).…”

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.…”