Fgfr1 and Fgfr2 have distinct differentiation- and proliferation-related roles in the developing mouse skull vault

Fibroblast growth factor receptors (FGFRs) play major roles in skeletogenes is, and activating mutations of the human FGFR1, FGFR2 and FGFR3 genes caus e premature fusion of the skull bones (craniosynostosis), We have investiga ted the patterns of expression of Fgfr1, Fgfr2 and Fgfr3 in the fetal mouse head, with specific reference to their relationship to cell proliferation and differentiation in the frontal and parietal bones and in the coronal su ture, Fgfr2 is expressed only in proliferating osteoprogenitor cells; the o nset of differentiation is preceded by downregulation of Fgfr2 and up-regul ation of Fgfr1, Following up-regulation of the differentiation marker osteo pontin, Fgfr1, osteonectin and alkaline phosphatase are downregulated, sugg esting that they are involved in the osteogenic differentiation process but not in maintaining the differentiated state. Fgfr3 is expressed in the cra nial cartilage, including a plate of cartilage underlying the coronal sutur e, as well as in osteogenic cells, suggesting a dual role in skull developm ent. Subcutaneous insertion of FGF2-soaked beads onto the coronal suture on E15 resulted in up-regulation of osteopontin and Fgfr1 in the sutural mese nchyme, down-regulation of Fgfr2, and inhibition of cell proliferation. Thi s pattern was observed at 6 and 24 hours after bead insertion, correspondin g to the timing and duration of FGF2 diffusion from the beads. We suggest ( a) that a gradient of FGF ligand, from high levels in the differentiated re gion to low levels in the environment of the osteogenic stem cells, modulat es differential expression of Fgfr1 and Fgfr2, and (b) that signalling thro ugh FGFR2 regulates stem cell proliferation whereas signalling through FGFR 1 regulates osteogenic differentiation.