Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis
- 5 December 2006
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 103 (49), 18603-18608
- https://doi.org/10.1073/pnas.0609157103
Abstract
Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, ≈20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). We describe a genetic and pharmacological approach for the treatment of a murine model system of Crouzon-like craniosynostosis induced by a dominant mutation in Fgfr2c. Using genetically modified mice, we demonstrate that premature fusion of sutures mediated by Crouzon-like activated Fgfr2c mutant is prevented by attenuation of signaling pathways by selective uncoupling between the docking protein Frs2α and activated Fgfr2c, resulting in normal skull development. We also demonstrate that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevents premature fusion of sutures without adversely affecting calvaria development. These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment.Keywords
This publication has 30 references indexed in Scilit:
- Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse developmentDevelopment, 2006
- The Docking Protein FRS2α Is an Essential Component of Multiple Fibroblast Growth Factor Responses during Early Mouse DevelopmentMolecular and Cellular Biology, 2005
- Mechanisms underlying differential responses to FGF signalingCytokine & Growth Factor Reviews, 2005
- Cellular signaling by fibroblast growth factor receptorsCytokine & Growth Factor Reviews, 2005
- Fibroblast growth factor signaling in tumorigenesisCytokine & Growth Factor Reviews, 2005
- Cranial skeletal biologyNature, 2003
- Craniosynostosis Syndromes: From Genes to Premature Fusion of Skull BonesMolecular Genetics and Metabolism, 1999
- Clinical spectrum of fibroblast growth factor receptor mutationsHuman Mutation, 1999
- Transforming Growth Factor βs and Fibroblast Growth Factors and Their Receptors: Role in Sutural Biology and CraniosynostosisJournal of Bone and Mineral Research, 1997
- TGF-β1, TGF-β2, and TGF-β3 Exhibit Distinct Patterns of Expression During Cranial Suture Formation and Obliteration In Vivo and In VitroJournal of Bone and Mineral Research, 1997