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Published online 21 March 2005. doi:10.1083/jcb.200409182
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 7, 1065-1076
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Article

Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation



Alka Mansukhani1, Davide Ambrosetti1,2, Greg Holmes1, Lizbeth Cornivelli1, and Claudio Basilico1

1 Department of Microbiology, New York University School of Medicine, New York, NY 10016
2 Department of Biology, University of Bologna, Bologna 40126, Italy

Correspondence to A. Mansukhani: mansua01{at}med.nyu.edu; or C. Basilico: basilc01{at}med.nyu.edu

Activating mutations in fibroblast growth factor receptor 2 (FGFR2) cause several craniosynostosis syndromes by affecting the proliferation and differentiation of osteoblasts, which form the calvarial bones. Osteoblasts respond to FGF with increased proliferation and inhibition of differentiation. We analyzed the gene expression profiles of osteoblasts expressing FGFR2 activating mutations (C342Y or S252W) and found a striking down-regulation of the expression of many Wnt target genes and a concomitant induction of the transcription factor Sox2. Most of these changes could be reproduced by treatment of osteoblasts with exogenous FGF. Wnt signals promote osteoblast function and regulate bone mass. Sox2 is expressed in calvarial osteoblasts in vivo and we show that constitutive expression of Sox2 inhibits osteoblast differentiation and causes down-regulation of the expression of numerous Wnt target genes. Sox2 associates with ß-catenin in osteoblasts and can inhibit the activity of a Wnt responsive reporter plasmid through its COOH-terminal domain. Our results indicate that FGF signaling could control many aspects of osteoblast differentiation through induction of Sox2 and regulation of the Wnt–ß-catenin pathway.

A. Mansukhani and D. Ambrosetti contributed equally to this paper.

Abbreviations used in this paper: ALP, alkaline phosphatase; AP, Apert; CR, Crouzon; FGFR, FGF receptor; HMG, high mobility group; LEF, lymphoid enhancer factor; TCF, T cell factor.


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