Study of Fibroblast Growth Factor Receptor Signalling during Skull Vault Development by Ex-Utero Surgery

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The experimental results suggest that maintenance of proliferating osteogenic cells at the margins of the membrane bones that form the coronal suture depends on low levels of FGF;high levels of FGF are associated with osteogenic differentiation. The proliferation signal is maintained by FGFR2 signalling. Higher levels of FGF/FGFR2 signalling result in down-regulation of FGFR2(and FGFR3), then the cells leave the cell cycle up-regulating of FGFR1, which leads to osteogenic differentiation. This balance is disturbed when FGF2 is applied to the mouse fetal sutural mesenchyme experimentally or when FGFR signalling is altered, e.g.in human craniosynostosis, in which FGFR2 is down-regulated and proliferation ceases. These conclusions are supported by the observation that FGF2 levels are increased within sutures at the time of fusion^<11)>. Also, FGFR2 immunoreactivity is reduced in the synostosed coronal sutures of Patients with Crouzon syndrome, which is due to activating mutation of FGFR2^<12)>. We suggest that(1)that in the coronal suture, the rate of progression from proliferation to differentiation is maintained by interaction between TWIST-regulated transcription, FGFR2/FGFR3 mitogenic signalling and FGFR1 differentiation-related signalling;(2)that differential levels of FGF2(and possibly other FGF ligands)play a key role in these interactions through regional regulation of expression of the receptor genes.
硬組織再生生物学会の論文