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Abstract

Wnt and Shh signaling pathways are critical for the development and maturation of many epithelial tissues. Both pathways have roles in stem cell maintenance, tissue development, and tumorigenesis. However, linkage between these pathways in mammalian systems had not been well established. Here, we report that Shh expression in fungiform papillae and formation of normal mature fungiform papillae depend on signaling through Wnt and β-catenin. We observed that during fungiform papilla formation in mice, Shh and components of the Wnt/β-catenin signaling pathway are expressed together in the developing placode. The elimination of Wnt/β-catenin signaling in either Lef1 or Wnt10b knockout mice resulted in down-regulation of Shh expression. In addition, the size and number of fungiform papillae were greatly reduced in Lef1 knockout mice. By examining embryonic mouse tongues in culture we determined that activation of Wnt/β-catenin signaling up-regulates Shh expression. We observed that blocking Shh signaling in cultured tongue explants enhanced papillae formation and was accompanied by an up-regulation of Wnt/β-catenin signaling, indicating that Shh inhibits the Wnt/β-catenin pathway. Exogenously added Shh suppressed expression of endogenous Shh and inhibited Wnt/β-catenin signaling (assessed in TOPGAL mice), further implicating Shh as an inhibitor of the Wnt/β-catenin pathway. Our observations indicate that Wnt/β-catenin signaling and interactions between the Wnt and Shh pathways play essential roles in the development of fungiform papillae.