Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in Faciogenital Dysplasia (FGDY; Aarskog syndrome)

FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically a ctivates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dyspla sia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adver sely affects the formation of multiple skeletal structures. To further defi ne the role of FGD1 in skeletal development, we examined its expression in developing mouse embryos and correlated this pattern with FC;DY skeletal de fects. In this study, we show that Fgd1, the mouse FGD1 ortholog, is initia lly expressed during the onset of ossification during embryogenesis. Fgd1 i s expressed in regions of active bone formation in the trabeculae and diaph yseal cortices of developing long bones. The onset of Fgd1 expression corre lates with the expression of bone sialoprotein, a protein specifically expr essed in osteoblasts at the onset of matrix mineralization; an analysis of serial sections shows that Fgd1 is expressed in tissues containing calcifie d and mineralized extracellular matrix. Fgd1 protein is specifically expres sed in cultured osteoblast and osteoblast-like cells including MC3T3-E1 cel ls and human osteosarcoma cells but not in other mesodermal cells; immunohi stochemical studies confirm the presence of Fgd1 protein in mouse calvarial cells, Postnatally, Fgd1 is expressed more broadly in skeletal tissue with expression in the perichondrium, resting chondrocytes, and joint capsule f ibroblasts. The data indicate that Fgd1 is expressed in a variety of region s of incipient and active endochondral and intramembranous ossification inc luding the craniofacial bones, vertebrae, ribs, long bones and phalanges, T he observed pattern of Fgd1 expression correlates with FGDY skeletal manife stations and provides an embryologic basis for the prevalence of observed s keletal defects. The observation that the induction of Fgd1 expression coin cides with the initiation of ossification strongly suggests that FGD1 signa ling plays a role in ossification and bone formation; it also suggests that FGD1 signaling does not play a role in the earlier phases of skeletogenesi s, With the observation that FGD1 mutations result in the skeletal dysplasi a FGDY, accumulated data indicate that FGD1 signaling plays a critical role in ossification and skeletal development. (C) 2000 Wiley-Liss, Inc.