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Stimulation of Notch Signaling in Mouse Osteoclast Precursors
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Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation

Alka Mansukhani1, Davide Ambrosetti, Greg Holmes

  • 1Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. mansua01@med.nyu.edu

The Journal of Cell Biology
|March 23, 2005
PubMed

Insights

Activating fibroblast growth factor receptor 2 (FGFR2) mutations disrupt bone development. FGF signaling induces Sox2, inhibiting osteoblast differentiation and Wnt pathway activity, impacting craniosynostosis syndromes.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Activating mutations in fibroblast growth factor receptor 2 (FGFR2) are linked to craniosynostosis syndromes.
  • FGFR2 signaling influences osteoblast proliferation and differentiation, crucial for calvarial bone formation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which FGFR2 mutations affect osteoblast gene expression.
  • To elucidate the role of Sox2 in mediating the effects of FGF signaling on osteoblast differentiation and Wnt pathway activity.

Main Methods:

  • Gene expression profiling of osteoblasts with activating FGFR2 mutations (C342Y, S252W).
  • Treatment of osteoblasts with exogenous FGF to mimic mutation effects.
  • Analysis of Sox2 expression, osteoblast differentiation markers, and Wnt target gene activity.
  • Co-immunoprecipitation to assess Sox2 and beta-catenin interaction.

Main Results:

  • FGFR2 mutations and FGF treatment down-regulated Wnt target genes and induced Sox2 expression in osteoblasts.
  • Constitutive Sox2 expression inhibited osteoblast differentiation and Wnt target gene expression.
  • Sox2 associated with beta-catenin and inhibited Wnt pathway reporter activity.

Conclusions:

  • FGF signaling regulates osteoblast differentiation, partly through Sox2 induction.
  • Sox2 plays a critical role in suppressing osteoblast differentiation by interfering with the Wnt-beta-catenin pathway.
  • These findings offer insights into the pathogenesis of FGFR2-related craniosynostosis syndromes.

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