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Mutations in the human fibroblast growth factor receptor type 2 (FGFR2) gene cause craniosynostosis, particularly affecting the coronal suture. We show here that, in the fetal mouse skull vault, Fgfr2 transcripts are most abundant at the periphery of the membrane bones; they are mutually exclusive with those of osteopontin (an early marker of osteogenic differentiation) but coincide with sites of rapid cell proliferation. Fibroblast growth factor type 2 (FGF2) protein, which has a high affinity for the FGFR2 splice variant associated with craniosynostosis, is locally abundant; immunohistochemical detection showed it to be present at low levels in Fgfr2 expression domains and at high levels in differentiated areas. Implantation of FGF2-soaked beads onto the fetal coronal suture by ex utero surgery resulted in ectopic osteopontin expression, encircled by Fgfr2 expression, after 48 hours. We suggest that increased FGF/FGFR signalling in the developing skull, whether due to FGFR2 mutation or to ectopic FGF2, shifts the cell proliferation/differentiation balance towards differentiation by enhancing the normal paracrine down-regulation of Fgfr2.


Journal article



Publication Date





3375 - 3384


Animals, Cell Differentiation, Cell Division, Cranial Sutures, Craniosynostoses, Female, Fibroblast Growth Factor 2, Gene Expression Regulation, Developmental, Humans, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Inbred C57BL, Models, Biological, Mutation, Osteogenesis, Osteopontin, Pregnancy, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Fibroblast Growth Factor, Sialoglycoproteins, Signal Transduction, Skull