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

<jats:p>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<jats:italic>Lef1</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> 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 <jats:italic>Lef1</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> tooth rudiments fails to express <jats:italic>Fgf4</jats:italic>, <jats:italic>Shh</jats:italic>, and<jats:italic>Bmp4</jats:italic>, but not <jats:italic>Wnt10a</jats:italic>. We identify the<jats:italic>Fgf4</jats:italic> gene as a direct transcriptional target for LEF1 and show that beads soaked with recombinant FGF4 protein can fully overcome the developmental arrest of <jats:italic>Lef1</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> tooth germs. In addition, we find that FGF4 beads induce rapidly the expression of <jats:italic>Fgf3</jats:italic> in dental mesenchyme and that both epithelial and mesenchymal FGF proteins induce the delayed expression of <jats:italic>Shh</jats:italic> 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.</jats:p>