Journal
DEVELOPMENTAL DYNAMICS
Volume 239, Issue 6, Pages 1888-1900Publisher
WILEY
DOI: 10.1002/dvdy.22314
Keywords
craniosynostosis; birth defects; FGF signaling; Fgfr2 IIIb and IIIc isoforms; craniofacial development; epithelial-mesenchymal interactions; mouse model for human diseases; hypoplastic maxilla; nasal septal cartilage; ligand-independent activation
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Funding
- Canadian Institutes of Health Research Centre for Modeling Human Disease [FRN69198]
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Missense mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) have been identified in human craniosynostotic syndromes such as Crouzon (CS) and Pfeiffer (PS). FGFR2 has two major isoforms, and IIIc, generated through alternative splicing with their own temporal, spatial, and ligand-binding specificities. In this study, we report the identification and characterization of a missense mutation in codon 290 of murine Fgfr2 (W290R). The defects in W290R mutants are suggestive of disruption of signalling in both IIIb and IIIc isoforms of the Fgfr2 gene. Heterozygous mutants presented with features resembling those found in patients with CS. Fgfr2(W290R) homozygotes displayed constitutive FGFR2 activation with increased, but correct tissue-specific, expression of the IIIb and IIIc isoforms in many of the defective organs. Our Fgfr2(W290R) mouse model thus represents an excellent mouse model of CS to probe the many questions around the pathogenesis of craniosynostotic birth defects consequent to defects in FGF signaling. Developmental Dynamics 239:1888-1900, 2010. (C) 2010 Wiley-Liss, Inc.
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