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Genes Dev
2004 May 01;189:1072-87. doi: 10.1101/gad.1171104.
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Interactions between Sox9 and beta-catenin control chondrocyte differentiation.
Akiyama H
,
Lyons JP
,
Mori-Akiyama Y
,
Yang X
,
Zhang R
,
Zhang Z
,
Deng JM
,
Taketo MM
,
Nakamura T
,
Behringer RR
,
McCrea PD
,
de Crombrugghe B
.
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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.
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15132997
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Figure 9.
(A,B) Sox9 inhibits β-catenin-mediated secondary-axis formation in Xenopus embryos. (A) Representative tail bud stage Xenopus embryos injected with the indicated RNAs into a single ventral-vegetal blastomere at the four-cell stage. (B) Summary of second axis assays from two separate experiments. Injection of mRNA encoding wild-type β-catenin (40 pg) results in a high frequency (77.8%) of embryos with secondary axes. Coinjection of increasing levels of Sox9 mRNA (0.5, 1.0, and 2.0 ng) with β-catenin (40 pg) results in a dose-dependent inhibition of β-catenin-induced secondary-axis formation. Sox9 (1-304) mRNA (2.0 ng) does not inhibit β-catenin-induced secondary-axis formation. Semiquantitative analysis of each embryo positive for a secondary axis (1 = weak, 2 = moderate, 3 = strong) further indicates that β-catenin-mediated secondary-axis formation is inhibited by increasing levels of Sox9, but not by Sox9 (1-304). (C) Proteasome inhibitor, MG132, restores the levels of β-catenin and Sox9 in 293 cells transfected with 6x myc-tagged stβ-catenin and 3xHA-tagged Sox9. Mutant Sox9 (1-304) does not decrease the levels of β-catenin, and MG132 has no effect on the levels of either β-catenin or Sox9 in these experiments.
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