Wnt/beta-catenin signaling in oral tissue development and disease

Abstract

The Wnt/beta-catenin signaling pathway is one of several key conserved intercellular signaling pathways in animals, and plays fundamental roles in the proliferation, regeneration, differentiation, and function of many cell and tissue types. This pathway is activated in a dynamic manner during the morphogenesis of oral organs, including teeth, taste papillae, and taste buds, and is essential for these processes to occur normally. Conversely, forced activation of Wnt/beta-catenin signaling promotes the formation of ectopic teeth and taste papillae. In this review, we discuss our current understanding of the roles of Wnt/beta-catenin signaling in oral tissue development and in related human diseases, and the potential of manipulating this pathway for therapeutic purposes.

Figure 1.

Simplified schematic of the Wnt/β-catenin signaling pathway. (Left) In the absence of a WNT ligand, cytoplasmic β-catenin is associated with APC and Axin, phosphorylated by GSK3β and CKI, and polyubiquitinated by the βTRCP complex, targeting it for proteosomal degradation; under these conditions, LEF/TCF transcription factors in the nucleus associate with transcriptional co-repressors, such as Groucho, and the transcription of Wnt target genes is repressed. (Right) In the presence of a WNT ligand, phosphorylation and degradation of β-catenin are inhibited, allowing it to accumulate in the cytoplasm and translocate into the nucleus. Nuclear β-catenin interacts with LEF/TCF family transcription factors and several other transcriptional co-activators to initiate transcription of target genes. Abbreviations: FZD, Frizzled; LRP, low-density lipoprotein-receptor-related protein; APC, adenomatous polyposis coli; GSK, glycogen synthase kinase; CKI, casein kinase I; DSH, Disheveled; LEF/TCF, Lymphoid enhancer factor/T-cell factor.

Figure 2.

The Wnt/β-catenin signaling pathway is activated in a dynamic fashion in molar tooth development. Summary of data from analyses of Wnt/β-catenin pathway activity in developing molar teeth in vivo with immunostaining for nuclear β-catenin; X-gal staining of embryos carrying Wnt reporter transgenes that contain multimerized LEF/TCF binding sites upstream of a minimal promoter and a lacZ reporter (TOPGAL, BAT-gal, and Lef/Tcf-lacZ); and X-gal staining of embryos in which lacZ has been inserted into the endogenous Axin2 locus, a direct Wnt target gene (Liu et al., 2008; Lohi et al., 2010). While expression patterns vary slightly for different reporters, these studies, taken together, indicate that Wnt/β-catenin signaling localizes specifically to the epithelium of the dental lamina at the placode stage; to the primary epithelial enamel knot and underlying mesenchymal cells at the bud and cap stages; and to the secondary enamel knots and underlying mesenchymal cells at the bell stage. Wnt/β-catenin pathway activity is indicated by grey or blue shading in the print and online versions, respectively. Dashed black lines indicate epithelial-mesenchymal borders. Diagrams are not to scale.