Interactions between Sox9 and -catenin control chondrocyte differentiation

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