title: Interactions between Sox9 and beta-catenin control chondrocyte differentiation.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. hakiyama@mdacc.tmc.edu
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Jon P
authors.initials: JP
authors.lastname: Lyons
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mori-Akiyama
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.forename: Ren
authors.initials: R
authors.lastname: Zhang
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Deng
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: Pierre D
authors.initials: PD
authors.lastname: McCrea
authors.forename: Benoit
authors.initials: B
authors.lastname: de Crombrugghe
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002455:Cell Division; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D006579:Heterozygote; D006609:High Mobility Group Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D055758:SOX9 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D029867:Xenopus Proteins; D014982:Xenopus laevis; D051176:beta Catenin
chemical_list: C495266:CTNNB1 protein, Xenopus; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D006609:High Mobility Group Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; D051176:beta Catenin; D019938:Cyclin D1