1. Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation
- Author
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Claudio Basilico, Alka Mansukhani, Davide Ambrosetti, Lizbeth Cornivelli, Greg Holmes, A. MANSUKHANI, D. AMBROSETTI, G. HOLMES, L. CORNIVELLI, and C. BASILICO.
- Subjects
Cellular differentiation ,Fibroblast growth factor ,Mice ,0302 clinical medicine ,Genes, Reporter ,Osteogenesis ,Research Articles ,beta Catenin ,Cell Line, Transformed ,Regulation of gene expression ,0303 health sciences ,biology ,Wnt signaling pathway ,Gene Expression Regulation, Developmental ,Osteoblast ,Cell Differentiation ,DNA-Binding Proteins ,medicine.anatomical_structure ,Synostosis ,030220 oncology & carcinogenesis ,Intercellular Signaling Peptides and Proteins ,Signal transduction ,Signal Transduction ,musculoskeletal diseases ,Transcriptional Activation ,Beta-catenin ,Down-Regulation ,Article ,03 medical and health sciences ,medicine ,Animals ,Receptor, Fibroblast Growth Factor, Type 2 ,030304 developmental biology ,Osteoblasts ,Fibroblast growth factor receptor 2 ,SOXB1 Transcription Factors ,Skull ,Receptor Protein-Tyrosine Kinases ,Cell Biology ,Receptors, Fibroblast Growth Factor ,Protein Structure, Tertiary ,Fibroblast Growth Factors ,Wnt Proteins ,Cytoskeletal Proteins ,Gene Expression Regulation ,Mutation ,biology.protein ,Cancer research ,Trans-Activators ,Transcription Factors - Abstract
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.
- Published
- 2005