Interactions between Sox9 and β-catenin control chondrocyte differentiation

Genes and Development - Tập 18 Số 9 - Trang 1072-1087 - 2004
Haruhiko Akiyama1, Jon P. Lyons2,3, Yuko Mori–Akiyama1, Xiaohong Yang1, Ren Zhang1,3, Zhaoping Zhang, Jian Min Deng1, Makoto M. Taketo1,4, Takashi Nakamura5, Richard R. Behringer1,3, Pierre D. McCrea2,3, Benoît De Crombrugghe1,3
1Department of Molecular Genetics
2Department of Biochemistry and Molecular Biology and
3Graduate Program in Genes & Development, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
4Department of Pharmacology, and
5Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

Tóm tắt

Chondrogenesis is a multistep process that is essential for endochondral bone formation. Previous results have indicated a role for β-catenin and Wnt signaling in this pathway. Here we show the existence of physical and functional interactions between β-catenin and Sox9, a transcription factor that is required in successive steps of chondrogenesis. In vivo, either overexpression of Sox9 or inactivation of β-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 β-catenin in chondrocytes also produces a similar phenotype of severe chondrodysplasia. Sox9 markedly inhibits activation of β-catenin-dependent promoters and stimulates degradation of β-catenin by the ubiquitination/proteasome pathway. Likewise, Sox9 inhibits β-catenin-mediated secondary axis induction in Xenopus embryos. β-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 β-catenin, followed by degradation of β-catenin. Our results strongly suggest that chondrogenesis is controlled by interactions between Sox9 and the Wnt/β-catenin signaling pathway.

Từ khóa


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