Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis

Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several human skeletal dysplasias, including the most common form of dwarf ism, achondroplasia. Here we show that a glycine-to-cysteine substitution a t position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimeriz ation and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimic king human achondroplasia. Accordingly, homozygous mice were more severely affected than heterozygotes. The resulting mutant mice exhibited macrocepha ly and shortened limbs due to retarded endochondral bone growth and prematu re closure of cranial base synchondroses. Compared with their wild-type lit termates, mutant mice growth plates shared an expanded resting zone and nar rowed proliferating and hypertrophic zones, which is correlated with the ac tivation of Stat proteins and upregulation of cell-cycle inhibitors. Reduce d bone density is accompanied by increased activity of osteoclasts and upre gulation 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 e ndochondral ossification.