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 β-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–β-catenin pathway.
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28 March 2005
Article|
March 21 2005
Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation
Alka Mansukhani,
Alka Mansukhani
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Davide Ambrosetti,
Davide Ambrosetti
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
2Department of Biology, University of Bologna, Bologna 40126, Italy
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Greg Holmes,
Greg Holmes
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Lizbeth Cornivelli,
Lizbeth Cornivelli
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Claudio Basilico
Claudio Basilico
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
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Alka Mansukhani
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
Davide Ambrosetti
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
2Department of Biology, University of Bologna, Bologna 40126, Italy
Greg Holmes
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
Lizbeth Cornivelli
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
Claudio Basilico
1Department of Microbiology, New York University School of Medicine, New York, NY 10016
Correspondence to A. Mansukhani: [email protected]; or C. Basilico: [email protected]
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.
Received:
September 29 2004
Accepted:
January 20 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 168 (7): 1065–1076.
Article history
Received:
September 29 2004
Accepted:
January 20 2005
Citation
Alka Mansukhani, Davide Ambrosetti, Greg Holmes, Lizbeth Cornivelli, Claudio Basilico; Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation . J Cell Biol 28 March 2005; 168 (7): 1065–1076. doi: https://doi.org/10.1083/jcb.200409182
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