Interactions between Sox9 and β-catenin control chondrocyte differentiation
- Haruhiko Akiyama1,6,
- Jon P. Lyons2,3,
- Yuko Mori-Akiyama1,
- Xiaohong Yang1,
- Ren Zhang1,3,
- Zhaoping Zhang1,
- Jian Min Deng1,
- Makoto M. Taketo4,
- Takashi Nakamura5,
- Richard R. Behringer1,3,
- Pierre D. McCrea2,3, and
- Benoit de Crombrugghe1,3,7
- 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
Abstract
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.
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Footnotes
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1171104.
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Corresponding authors.
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↵6 E-MAIL hakiyama{at}mdacc.tmc.edu; FAX (713) 794-4295.
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↵7 E-MAIL bdecromb{at}mail.mdanderson.org; FAX (713) 794-4295.
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- Accepted March 22, 2004.
- Received November 21, 2003.
- Cold Spring Harbor Laboratory Press