TheIIIcalternative ofFgfr2is a positive regulator of bone formation

Abstract

Fibroblast growth factor receptor type 2 (FGFR2) plays major roles in development. Like FGFR1 and FGFR3, it exists as two splice variants, IIIb and IIIc. We have investigated in the mouse the function of FGFR2IIIc, the mesenchymal splice variant of FGFR2. Fgfr2IIIc is expressed in early mesenchymal condensates and in the periosteal collar around the cartilage models; later it is expressed in sites of both endochondral and intramembranous ossification. A translational stop codon inserted into exon 9 disrupted the synthesis of Fgfr2IIIc without influencing the localized transcription of Fgfr2IIIb, the epithelial Fgfr2 variant. The recessive phenotype of Fgfr2IIIc–/– mice was characterized initially by delayed onset of ossification, with continuing deficiency of ossification in the sphenoid region of the skull base. During subsequent stages of skeletogenesis, the balance between proliferation and differentiation was shifted towards differentiation, leading to premature loss of growth, synostosis in certain sutures of the skull base and in the coronal suture of the skull vault, with dwarfism in the long bones and axial skeleton. The retarded ossification was correlated with decrease in the localized transcription of the osteoblast markers secreted phosphoprotein 1 (Spp1) and Runx2/Cbfa1. A decrease in the domain of transcription of the chondrocyte markers Ihh and PTHrP (Pthlh) corresponded with a decrease in their transcripts in the proliferative and hypertrophic chondrocyte zones. These results suggest that Fgfr2IIIc is a positive regulator of ossification affecting mainly the osteoblast, but also the chondrocyte, lineages. This role contrasts with the negative role of Fgfr3, although recent reports implicate FGF18, a ligand for FGFR3IIIc and FGFR2IIIc, as a co-ordinator of osteogenesis via these two receptors.

Srsf3 mediates alternative RNA splicing downstream of PDGFRα signaling in the facial mesenchyme

“…Fgfr2 is subject to AS that produces tissue-specific isoforms depending on the inclusion of exon 8 (epithelial 'b' isoforms) or exon 9 (mesenchymal 'c' isoforms). Both isoforms are required for proper craniofacial development (De Moerlooze et al, 2000;Eswarakumar et al, 2002). Analysis of Fgfr2 expression from RNA isolated from the facial processes of E12.5 control and cKO embryos revealed that both epithelia-and mesenchyme-specific splice isoforms were observed in each genotype (Fig.…”

Genomic adaptations for arboreal locomotion in Asian flying treefrogs

“…4 A ). For example, FGFR2 , which is expressed in the limb ectoderm, apical ectodermal ridge, skeletal anlagen, perichondrium, and periosteum, is necessary for limb formation, with loss of isoform FGFR2 IIIc or gain-of-function mutations in FGFR2 resulting in shortened limbs and digits ( 17 , 18 ). Furthermore, FBN2 knockout mice have shorter limb bones than wild-type mice ( 19 ).…”

Systems Biology Approach to the Origin of the Tetrapod Limb

“…FGFs are also often mentioned as a candidate [79], but there is no evidence for the colocalization of their signal with condensations. Although an FGF receptor, Fgfr2 (more precisely its IIIc isoform) is expressed in the prechondrogenic mesenchyme [89,90], the loss of Fgfr2 in the limb mesenchyme affects only a minor growth defect [91]. Similarly, no patterning defects are also observed in the limbs lacking galectins (e.g., [92]), which were proposed as Turing molecules to explain digit patterning in chick embryos.…”