Skeletal-specific expression ofFgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome)

Abstract

FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. To further define the role of FGD1 in skeletal development, we examined its expression in developing mouse embryos and correlated this pattern with FGDY skeletal defects. In this study, we show that Fgd1, the mouse FGD1 ortholog, is initially expressed during the onset of ossification during embryogenesis. Fgd1 is expressed in regions of active bone formation in the trabeculae and diaphyseal cortices of developing long bones. The onset of Fgd1 expression correlates with the expression of bone sialoprotein, a protein specifically expressed in osteoblasts at the onset of matrix mineralization; an analysis of serial sections shows that Fgd1 is expressed in tissues containing calcified and mineralized extracellular matrix. Fgd1 protein is specifically expressed in cultured osteoblast and osteoblast-like cells including MC3T3-E1 cells and human osteosarcoma cells but not in other mesodermal cells; immunohistochemical 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 fibroblasts. The data indicate that Fgd1 is expressed in a variety of regions of incipient and active endochondral and intramembranous ossification including the craniofacial bones, vertebrae, ribs, long bones and phalanges. The observed pattern of Fgd1 expression correlates with FGDY skeletal manifestations and provides an embryologic basis for the prevalence of observed skeletal defects. The observation that the induction of Fgd1 expression coincides with the initiation of ossification strongly suggests that FGD1 signaling plays a role in ossification and bone formation; it also suggests that FGD1 signaling does not play a role in the earlier phases of skeletogenesis. With the observation that FGD1 mutations result in the skeletal dys-plasia FGDY, accumulated data indicate that FGD1 signaling plays a critical role in ossification and skeletal development.

Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function

“…In addition to controlling Rho signaling, FAK functions in the regulation of Cdc42 and Rac activity for control cellular polarization, the extension of lamellipodia, and cell migration through the modulation of a so-called paxillin kinase linker (PKL/Git2)-β-pix complex [155]. On a side note, the GEF that activates Cdc42, termed FGD1, not only regulates the actin cytoskeleton [162], but is also the locus for facio-genital dysplasia (Aarskog-Scott syndrome) [163,164], highlighting the in vivo relevance of the regulation of actin dynamics.…”

A novel, putatively null, FGD1 variant leading to Aarskog-Scott syndrome in a family from UAE

“…FGD1 belongs to the DBL family of proteins and is considered essential for normal embryogenesis in mammals; with an important role in skeletal development and morphogenesis. Additionally, FGD1 is a potential regulator of extracellular matrix remodeling, which is strongly connected to its roles in cytoskeletal organization [2, 3]. …”

FGD1 Variant Associated With Aarskog–Scott Syndrome

“…Consistent with the previous study showing negative mutants of CDC42 inhibit CDC42 signaling and suppressed osteogenesis, our study manifests the attenuated CDC42 signaling in skeletal dysplasia ( 41 ). Although dysregulation of the FGD1/CDC42 signaling pathway is suspected to be associated with skeletal defects in AAS, whether the downstream signaling molecules and the mechanism of mutations in FGD1 might influence bone development remain to be elucidated ( 42 ). It is well-known that CDC42 regulates MAPK signaling pathways, including P38, ERK, and JNK, that might have an important impact on numerous cellular activities.…”