Blocking endogenous FGF-2 activity prevents cranial osteogenesis.
Normal growth and morphogenesis of the cranial vault reflect a balance between cell proliferation in the sutures and osteogenesis at the margins of the cranial bones. In the clinical condition craniosynostosis, the sutures fuse prematurely as a result of precocious osteogenic differentiation and craniofacial malformation results. Mutations in several fibroblast growth factor receptor (FGFR) genes have now been identified as being responsible for the major craniosynostotic syndromes. We have used a grafting technique to manipulate the levels of endogenous FGF-2 ligand in embryonic chick cranial vaults and thereby perturb morphogenesis. Implantation of beads loaded with FGF-2 did not affect normal cranial development at physiological concentrations, although they elicited a morphogenetic response in the limb. Implantation of beads loaded with a neutralising antibody to FGF-2 generated a concentration-dependent response. When a single bead was implanted, the grafts grew to a massive size as a result of increased cell division in the tissue. With greater inactivation of FGF-2 protein (two to three beads implanted), all further bone differentiation and cell proliferation was blocked. These data further support the emerging idea that the intensity of FGF-mediated signalling determines the developmental fate of the skeletogenic cells in the cranial vault. High and low levels correlate with differentiation and proliferation, respectively. A balance between the two ensures normal cranial vault morphogenesis. This is consistent with the observation that several FGFR mutations causing craniosynostosis result in constitutive activation of the receptor.
Moore
Rachel
R
Developmental Biology Unit, University College London, London, WC1N 1EH, United Kingdom.
Ferretti
Patrizia
P
Copp
Andrew
A
Thorogood
Peter
P
D000818:Animals; D002642:Chick Embryo; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000166:cytology / Q000196:embryology* / Q000502:physiology
D016222:Fibroblast Growth Factor 2