Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cranial Sutures / embryology
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Craniosynostoses / embryology
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Craniosynostoses / genetics
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Craniosynostoses / metabolism
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Female
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology*
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Gene Expression Regulation, Developmental / drug effects
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Humans
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Immunohistochemistry
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In Situ Hybridization
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Mice
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Mice, Inbred C57BL
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Models, Biological
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Mutation
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Osteogenesis / genetics
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Osteopontin
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Pregnancy
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor, Fibroblast Growth Factor, Type 2
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Receptors, Fibroblast Growth Factor / genetics*
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Receptors, Fibroblast Growth Factor / metabolism
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Sialoglycoproteins / genetics*
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Sialoglycoproteins / metabolism
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Signal Transduction
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Skull / drug effects
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Skull / embryology*
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Skull / metabolism*
Substances
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Receptors, Fibroblast Growth Factor
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SPP1 protein, human
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Sialoglycoproteins
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Spp1 protein, mouse
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Fibroblast Growth Factor 2
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Osteopontin
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FGFR2 protein, human
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Fgfr2 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 2