Fgfr2 and osteopontin domains in the developing skull vault are mutually exclusive and can be altered by locally applied FGF2.
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.
Iseki
S
S
Department of Human Anatomy, Oxford, UK.
Wilkie
A O
AO
Heath
J K
JK
Ishimaru
T
T
Eto
K
K
Morriss-Kay
G M
GM
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003393:Cranial Sutures / Q000196:embryology; D003398:Craniosynostoses / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D010012:Osteogenesis / Q000235:genetics; D053495:Osteopontin; D011247:Pregnancy; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*
D017468:Receptors, Fibroblast Growth Factor; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D016222:Fibroblast Growth Factor 2; D053495:Osteopontin; C496353:FGFR2 protein, human; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2