Interactions between Sox9 and β-catenin control chondrocyte differentiation

By H. Akiyama, Jon P. Lyons, Yuko Mori‐Akiyama, Xiaohong Yang, Ren Zhang, Zhaoping Zhang, J. Deng, M. Taketo, Takashi Nakamura, R. Behringer and 2 more. 2004

692 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/85585a483dc3a46230f65a62091bb0c4560893a9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Andrea Augello
2. C. De Bari

In Molecular Biology

1. Fanxin Long
2. D. Ornitz
3. Andrew P. McMahon
4. Kai Yu
5. Andrea Augello
6. C. De Bari
7. Stephen J. Rodda
8. T. Komori

In Rheumatology

1. Andrea Augello
2. C. De Bari

Citations in the corpus

• Mechanisms underlying differential responses to FGF signaling. (2005, background): “Support for this hypothesis comes from mouse genetic experiments showing that overexpression of Sox9 or the inactivation of b-catenin result in similar phenotypes of dwarfism with reduced chondrocyte proliferation, and delayed differentiation [114].”
• Sequential roles of Hedgehog and Wnt signaling in osteoblast development (2004, background): “The defects in chondrocyte maturation and proliferation described here are similar to that observed in the Col2a1-Cre; β-cateninc/c mutant (Akiyama et al., 2004).”
• Development of the endochondral skeleton. (2013, background): “Conditional overexpression of a stabilized b-catenin by Col2a1-Cre can lead to severe achondrodysplasia (Akiyama et al. 2004).”
• Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors (2006, background): “On the basis of these interactions, it has been proposed that Sox9 inhibits -catenin activity, promoting -catenin degradation (Akiyama et al., 2004), such that overexpression of Sox9 generates a similar phenotype to loss-of-function of - catenin.”
• The Regulation of Differentiation in Mesenchymal Stem Cells (2010, positive): “…intervening in osteogenic differentiation are CBFA-1/Runx2 and Osterix (Osx), known to be required for bone formation during development (Schroeder et al. , 2005; Komori, 2010), whereas Sox9 is a transcription factor required for cartilage formation (Akiyama et al. , 2004; Quintana et al. , 2009).”
• Activation of β-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult β-Catenin Conditional Activation Mice (2008, background): “The delayed development of hypertrophic chondrocytes and ossification in the radius, reduced chondrocyte proliferation, and delayed blood vessel invasion in the growth plates were observed in these conditional knockout (cKO) mice.((7,8)) Conditional activation of the -catenin gene in chondrocytes (t”