Article

Uncoupling Fibroblast Growth Factor receptor 2 ligand binding specificity leads to Apert syndrome-like phenotypes

Washington University in St. Louis, San Luis, Missouri, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2001; 98(7). DOI: 10.1073/pnas.081082498
Source: PubMed Central
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Available from: David Ornitz, Jan 25, 2014
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    • "Defects in FGF signaling in the mesenchymal condensation can result in skeletal abnormalities. For example, in the case of Apert Syndrome, mutations in FGFR2 allow for inappropriate activation of FGFR2 in the mesenchymal condensation by mesenchymally expressed ligands, such as FGF7 and FGF10, that normally do not signal to this receptor [83] [84]. Although ligand-binding specificity is also lost for epithelial forms of FGFR2, the recent identification of mutations within the mesenchymal-specific c exon of Fgfr2 (A315S) that allow binding to FGF10, suggests that the primary etiology of Apert syndrome results from inappropriate activation of the mesenchymal receptor [85] [39]. "
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    ABSTRACT: Mutations in fibroblast growth factor receptors (Fgfrs) are the etiology of many craniosynostosis and chondrodysplasia syndromes in humans. The phenotypes associated with these human syndromes and the phenotypes resulting from targeted mutagenesis in the mouse have defined essential roles for FGF signaling in both endochondral and intramembranous bone development. In this review, I will focus on the role of FGF signaling in chondrocytes and osteoblasts and how FGFs regulate the growth and development of endochondral bone.
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    • "This mutation is an interesting example of defects that may result from the inappropriate localization or abnormal binding specificity of the Fgfr2 alternatives. Such defects have been associated with Apert syndrome (Anderson et al., 1998; Oldridge et al., 1999; Yu and Ornitz, 2001). In contrast, the creation of a translational stop codon in exon 9, as described here, did not affect the localized transcription of the IIIb splice variant, which uses exon 8. "
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    ABSTRACT: Fibroblast growth factor receptor type 2 (FGFR2) plays major roles in development. Like FGFR1 and FGFR3, it exists as two splice variants, IIIb and IIIc. We have investigated in the mouse the function of FGFR2IIIc, the mesenchymal splice variant of FGFR2. Fgfr2IIIc is expressed in early mesenchymal condensates and in the periosteal collar around the cartilage models; later it is expressed in sites of both endochondral and intramembranous ossification. A translational stop codon inserted into exon 9 disrupted the synthesis of Fgfr2IIIc without influencing the localized transcription of Fgfr2IIIb, the epithelial Fgfr2 variant. The recessive phenotype of Fgfr2IIIc(-/-) mice was characterized initially by delayed onset of ossification, with continuing deficiency of ossification in the sphenoid region of the skull base. During subsequent stages of skeletogenesis, the balance between proliferation and differentiation was shifted towards differentiation, leading to premature loss of growth, synostosis in certain sutures of the skull base and in the coronal suture of the skull vault, with dwarfism in the long bones and axial skeleton. The retarded ossification was correlated with decrease in the localized transcription of the osteoblast markers secreted phosphoprotein 1 (Spp1) and Runx2/Cbfa1. A decrease in the domain of transcription of the chondrocyte markers Ihh and PTHrP (Pthlh) corresponded with a decrease in their transcripts in the proliferative and hypertrophic chondrocyte zones. These results suggest that Fgfr2IIIc is a positive regulator of ossification affecting mainly the osteoblast, but also the chondrocyte, lineages. This role contrasts with the negative role of Fgfr3, although recent reports implicate FGF18, a ligand for FGFR3IIIc and FGFR2IIIc, as a co-ordinator of osteogenesis via these two receptors.
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