Wnt signaling promotes tooth germ development through YAP1-TGF-β signaling

Tooth germ development involves continuous and sequential steps with reciprocal interactions between odontogenic epithelium and the adjacent mesenchyme. Several growth factors, including Wnt, are essential for tooth germ development. Molecular mechanisms underlying Wnt/β-catenin-regulated tooth germ development are poorly understood. In tooth germ rudiments culture, we recently demonstrated that Semaphorin 3A (Sema3A), an axonal guidance factor, stimulation reversed Wnt/β-catenin signaling-dependent decreased cell proliferation but did not completely rescue the morphological anomalies of tooth germ, suggesting that an uncharacterized signaling pathway may be essential in Wnt/β-catenin signaling-dependent tooth germ development. Herein, an enrichment analysis using DNA microarray data, which was obtained in our previous research, revealed that Wnt/β-catenin signaling negatively regulates YAP1 and/or TGF-β signalings. In odontogenic epithelial cells and tooth germ rudiments, Wnt/β-catenin signaling activation reduced YAP1 expression, thereby suppressing YAP1 and TGF-β signalings sequentially. Additionally, YAP1 signaling induced TGF-β2 expression to promote TGF-β signaling in the cells. Finally, Wnt/β-catenin signaling-dependent disorganized tooth germ development, in which YAP1 signaling was suppressed, was reversed by TGF-β stimulation. These results suggest that Wnt/β-catenin signaling contributes to the tooth germ development through YAP1-TGF-β signaling.