Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis
Lin Chen, … , Avner Yayon, Chu-Xia Deng
Lin Chen, … , Avner Yayon, Chu-Xia Deng
Published December 1, 1999
Citation Information: J Clin Invest. 1999;104(11):1517-1525. https://doi.org/10.1172/JCI6690.
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 1

Options: View larger image (or click on image) Download as PowerPoint
Introduction of Gly369Cys mutation into the mouse Fgfr3 locus. (a) Targe...
Introduction of Gly369Cys mutation into the mouse Fgfr3 locus. (a) Targeting construct, pFgfr3-Gly369Cys, contained the Gly369Cys mutation in exon 10 and a pLoxpneo gene in intron 10 of the Fgfr3 gene. Of 120 G418r/FIAUr clones examined by Southern blot analysis using a 5′ flanking probe (probe 1), 5 clones showed an extra fragment of approximately 11 kb upon NotI + EcoRV digestion (c). The targeting events were confirmed by XbaI +EcoRV digestion using a 3′ internal probe (probe 2). Three of them had the point mutation co-transferred as indicated by sequencing (unpublished observations). (b) Removal of the pLoxpneo gene by breeding with EIIa-cre transgenic mice. The Cre-mediated deletion was genotyped by PCR as described in the Methods section.