Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis
Lin Chen, Rivka Adar, Xiao Yang, Efrat O. Monsonego, Cuiling Li, Peter V. Hauschka, Avner Yayon, Chu-Xia Deng
Lin Chen, Rivka Adar, Xiao Yang, Efrat O. Monsonego, Cuiling Li, Peter V. Hauschka, Avner Yayon, Chu-Xia Deng
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Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis

Abstract

Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several human skeletal dysplasias, including the most common form of dwarfism, achondroplasia. Here we show that a glycine-to-cysteine substitution at position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human achondroplasia. Accordingly, homozygous mice were more severely affected than heterozygotes. The resulting mutant mice exhibited macrocephaly and shortened limbs due to retarded endochondral bone growth and premature closure of cranial base synchondroses. Compared with their wild-type littermates, mutant mice growth plates shared an expanded resting zone and narrowed proliferating and hypertrophic zones, which is correlated with the activation of Stat proteins and upregulation of cell-cycle inhibitors. Reduced bone density is accompanied by increased activity of osteoclasts and upregulation of genes that are related to osteoblast differentiation, including osteopontin, osteonectin, and osteocalcin. These data reveal an essential role for FGF/FGFR3 signals in both chondrogenesis and osteogenesis during endochondral ossification.

Authors

Lin Chen, Rivka Adar, Xiao Yang, Efrat O. Monsonego, Cuiling Li, Peter V. Hauschka, Avner Yayon, Chu-Xia Deng

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Ligand-independent dimerization and activation of G375C mutant FGFR3. (a...
Ligand-independent dimerization and activation of G375C mutant FGFR3. (a) Wild type, G380R, S371C, G375C and K650E mutants of FGFR3 were transiently expressed in 293T cells in the absence or presence of 50 ng/ml aFGF, lysed and immunoprecipitated with anti FGFR3 antibody. Blots were developed using anti-FGFR3 antiserum (upper panel) or anti-phosphotyrosine antibody (lower panel). (b) Receptor phosphotyrosine activity normalized for expression levels of FGFR3. In the absence of aFGF, FGFR3 mutants corresponding to the immunoblot above are phosphorylated. The K650E mutant has the highest basal activity, the G371C mutant is lower in basal activity but still higher than G375C and both are significantly higher than that of the wild type receptor. (c) Wild type and mutant FGFR3 transiently expressed in 293T cells were subjected to chemical cross-linking after being stimulated with 50 ng/ml aFGF. Ligand-independent receptor dimers were found for the S371C and G375C mutants, but not in the wild-type receptor.