The Balance of WNT and FGF Signaling Influences Mesenchymal Stem Cell Fate During Skeletal Development

Sci. Signal., 25 May 2010
Vol. 3, Issue 123, p. ra40
DOI: 10.1126/scisignal.2000727

The Balance of WNT and FGF Signaling Influences Mesenchymal Stem Cell Fate During Skeletal Development

  1. Takamitsu Maruyama1,
  2. Anthony J. Mirando1,
  3. Chu-Xia Deng2, and
  4. Wei Hsu1,3,*
  1. 1Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
  2. 2Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  3. 3James Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
  1. *To whom correspondence should be addressed. E-mail: wei_hsu{at}urmc.rochester.edu

Abstract

Craniosynostosis, a developmental disorder resulting from premature closure of the gaps (sutures) between skull bones, can be caused by excessive intramembranous ossification, a type of bone formation that does not involve formation of a cartilage template (chondrogenesis). Here, we show that endochondral ossification, a type of bone formation that proceeds through a cartilage intermediate, caused by switching the fate of mesenchymal stem cells to chondrocytes, can also result in craniosynostosis. Simultaneous knockout of Axin2, a negative regulator of the WNT–β-catenin pathway, and decreased activity of fibroblast growth factor (FGF) receptor 1 (FGFR1) in mice induced ectopic chondrogenesis, leading to abnormal suture morphogenesis and fusion. Genetic analyses revealed that activation of β-catenin cooperated with FGFR1 to alter the lineage commitment of mesenchymal stem cells to differentiate into chondrocytes, from which cartilage is formed. We showed that the WNT–β-catenin pathway directly controlled the stem cell population by regulating its renewal and proliferation, and indirectly modulated lineage specification by setting the balance of the FGF and bone morphogenetic protein pathways. This study identifies endochondral ossification as a mechanism of suture closure during development and implicates this process in craniosynostosis.

Citation:

T. Maruyama, A. J. Mirando, C.-X. Deng, and W. Hsu, The Balance of WNT and FGF Signaling Influences Mesenchymal Stem Cell Fate During Skeletal Development. Sci. Signal. 3, ra40 (2010).

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