Interactions between Sox9 and β-catenin control chondrocyte differentiation

作者：Haruhiko Akiyama, Jon P. Lyons, Yuko Mori–Akiyama, Xiaohong Yang, Ren Zhang, Zhaoping Zhang, Jian Min Deng, Makoto Mark Taketo, Takashi Nakamura, Richard R. Behringer, Pierre D. McCrea, Benoît De Crombrugghe · 发表于：Genes & Development · 年份：2004 · DOI：10.1101/gad.1171104 · 被引用次数：768 · 研究领域：Wnt/β-catenin signaling in development and cancer、NF-κB Signaling Pathways、Osteoarthritis Treatment and Mechanisms

Chondrogenesis is a multistep process that is essential for endochondral bone formation. Previous results have indicated a role for beta-catenin and Wnt signaling in this pathway. Here we show the existence of physical and functional interactions between beta-catenin and Sox9, a transcription factor that is required in successive steps of chondrogenesis. In vivo, either overexpression of Sox9 or inactivation of beta-catenin in chondrocytes of mouse embryos produces a similar phenotype of dwarfism with decreased chondrocyte proliferation, delayed hypertrophic chondrocyte differentiation, and endochondral bone formation. Furthermore, either inactivation of Sox9 or stabilization of beta-catenin in chondrocytes also produces a similar phenotype of severe chondrodysplasia. Sox9 markedly inhibits activation of beta-catenin-dependent promoters and stimulates degradation of beta-catenin by the ubiquitination/proteasome pathway. Likewise, Sox9 inhibits beta-catenin-mediated secondary axis induction in Xenopus embryos. Beta-catenin physically interacts through its Armadillo repeats with the C-terminal transactivation domain of Sox9. We hypothesize that the inhibitory activity of Sox9 is caused by its ability to compete with Tcf/Lef for binding to beta-catenin, followed by degradation of beta-catenin. Our results strongly suggest that chondrogenesis is controlled by interactions between Sox9 and the Wnt/beta-catenin signaling pathway.