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Development 129, 3783-3793 (2002)
© 2002 The Company of Biologists Limited

The IIIc alternative of Fgfr2 is a positive regulator of bone formation

Vereragavan P. Eswarakumar1, Efrat Monsonego-Ornan2, Mark Pines2, Ileana Antonopoulou3, Gillian M. Morriss-Kay3 and Peter Lonai1,*

1 Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot Israel
2 Institute for Animal Science, The Volcani Center, Beit Dagan, Israel
3 Department of Human Anatomy and Genetics, University of Oxford, Oxford, UK

*Author for correspondence (e-mail: peter.lonai{at}weizmann.ac.il)

Accepted 17 May 2002

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.

Key words: Transcriptional alternatives, FGF, Endochondral ossification, Craniosynostosis, Gene targeting, Mouse






© The Company of Biologists Ltd 2002