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
View: Text | PDF
Article

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

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
Histology and immunohistochemistry analyses of growth plates of P15 mice...
Histology and immunohistochemistry analyses of growth plates of P15 mice. Genotypes and markers were as indicated. (a) Chondrocytes in the WT growth plates are divided into 4 distinct zones, i.e. resting (Rc), proliferating (Pc), maturing (Mc) and hypertrophic (Hc) chondrocytes. (b and c) In the mutant growth plates, the demarcation of each zone is not clear. Arrows point to the secondary ossification center. (d–f) [3H]Thymidine incorporation. The labeled cells in WT mark the Pc zone. In mutant growth plates, the labeled cells are fewer in number and scattered, suggesting that the majority of the cells are in a quiescent state. (g–o) Immunohistochemical analysis of growth plates, using antibodies to FGFR3 (g–i), Stat5b (j–l, and m–o for higher magnification), and p19 (p–r). In all cases, the staining was the weakest in WT, intermediate in 369/+, and strongest in 369/369 growth plates.