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Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis.
Proc Natl Acad Sci U S A 2006; 103(49):18603-8PN

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, approximately 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 Frs2alpha 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.

Authors+Show Affiliations

Department of Pharmacology and Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17132737

Citation

Eswarakumar, V P., et al. "Attenuation of Signaling Pathways Stimulated By Pathologically Activated FGF-receptor 2 Mutants Prevents Craniosynostosis." Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 49, 2006, pp. 18603-8.
Eswarakumar VP, Ozcan F, Lew ED, et al. Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proc Natl Acad Sci USA. 2006;103(49):18603-8.
Eswarakumar, V. P., Ozcan, F., Lew, E. D., Bae, J. H., Tomé, F., Booth, C. J., ... Schlessinger, J. (2006). Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. Proceedings of the National Academy of Sciences of the United States of America, 103(49), pp. 18603-8.
Eswarakumar VP, et al. Attenuation of Signaling Pathways Stimulated By Pathologically Activated FGF-receptor 2 Mutants Prevents Craniosynostosis. Proc Natl Acad Sci USA. 2006 Dec 5;103(49):18603-8. PubMed PMID: 17132737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis. AU - Eswarakumar,V P, AU - Ozcan,F, AU - Lew,E D, AU - Bae,J H, AU - Tomé,F, AU - Booth,C J, AU - Adams,D J, AU - Lax,I, AU - Schlessinger,J, Y1 - 2006/11/28/ PY - 2006/11/30/pubmed PY - 2007/2/3/medline PY - 2006/11/30/entrez SP - 18603 EP - 8 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 103 IS - 49 N2 - 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, approximately 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 Frs2alpha 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. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/17132737/Attenuation_of_signaling_pathways_stimulated_by_pathologically_activated_FGF_receptor_2_mutants_prevents_craniosynostosis_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17132737 DB - PRIME DP - Unbound Medicine ER -