Moore, Rachel Louise; (1999) Experimental analyses of the roles of the fibroblast growth factor family in skeletogenesis. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Craniosynostosis is a disease that afflicts approximately 1 in 2500 children worldwide. It is caused by the premature fusion of the cranial sutures which normally function as proliferation centres allowing the expansion of the skull during the growth of the brain and facial region. Affected children have major abnormalities including underdevelopment of the midface, limb defects, raised intracranial pressure, breathing problems as a result of airway restriction and severe learning difficulties. In 1994 a mutation in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene was found in patients with Crouzon syndrome, one of the craniosynostoses and subsequently mutations in FGFRs 1-3 have accounted for many of these syndromes. Very little is known to date about the mechanisms which generate normal and abnormal phenotypes and in this Thesis, a model system has been used to elucidate the developmental pathways responsible. A grafting technique has been used to manipulate developing embryonic chick crania and perturb morphogenesis. Implantation of beads soaked in the ligand FGF-2 did not affect normal cranial development at biological concentrations. In the limb bud however, these same beads elicited dramatic changes in morphogenesis demonstrating that these beads are biologically active. Implantation of beads soaked in a neutralising antibody to FGF-2 resulted in a graded response. When a single bead is implanted thereby reducing the active levels of endogenous FGF-2 protein, the grafts grew to a massive size as a result of increased cell division in the tissue. By using a technique to detect proliferating cell nuclei immunohistochemically it is clear that in these large grafts almost all nuclei are undergoing cell division whereas in control grafts the opposite is the case. With greater inactivation of FGF-2 protein (2-3 antiFGF-2 loaded beads implanted) further bone differentiation was blocked and the level of cell proliferation was reduced below background levels. It is proposed that a multi-stage signalling cascade operates within the skull such that at low levels of FGF, proliferation occurs and at higher levels, these cells are further induced to differentiate into bone. Conversely, when FGF is blocked and the amount available to receptors is reduced, cranial bone morphogenesis is prevented. These results relate to the clinical situation since the majority of mutations in FGFRs in patients with craniosynostosis are thought to result in increased receptor activation equivalent to an increase in FGF signalling. Hence the effect is premature differentiation of cranial sutures into bone.

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