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PUTATIVE GENES DOWNSTREAM OF FGFR2 CONTRIBUTING TO CORONAL SUTURE SYNOSTOSIS IN A C342Y CROUZON MURINE MODEL
Presenter: Samintharaj Kumar, MBBS BDS MRCS MFDSRCS MFDRCSI
Co-Authors: Peskett E; Britto JA; Pauws E
University College London Institute of Child Health

Crouzon syndrome (CS), featuring coronal synostosis within a range of phenotypic features, is most commonly caused by the activating C342Y mutation in FGFR2-IIIc. Whilst much is known about FGF signalling and the effect of FGFR2 activation upon sutural osteoblasts, little is known about the effect of FGFR2 signalling on target genes or downstream pathways as related to coronal suture fusion. A divergence in the morphology between wild-type (Wt) and Fgfr2C342Y/+ (Mut) calvaria was found after E17.5 suggesting that Mut E17.5 coronal sutures might be enriched for genes involved in the pathogenesis of coronal suture synostosis. Coronal suture with flanking frontal and parietal bone, was bilaterally micro-dissected from Wt and Mut mouse calvaria (n=5). Global expression profiles were analysed using Affymetrix microarrays. 51 identified candidate genes were differentially expressed by at least 1.5-fold (p<0.05). Furthermore, 5 genes (Dpt, Osr1, Nov, Dlk1 and Kera) were found to be downregulated up to 3.5-fold in the Mut. These findings were independently validated using Taqman qPCR. Previous studies report these genes as regulatory factors during osteoblast and/or chondrocyte differentiation, making them putative downstream targets of activated FGFR2 signalling in coronal synostosis. In-situ hybridizations for these genes in parasagittal sections from E15.5 to E18.5 Wt/Mut heads show that Osr1 is found in fronto-parietal osteogenic fronts outlining frontal and parietal bones, periosteum and skin. Dpt expression is expressed in dermis and periosteal outlines of the frontal bone. Nov is expressed in murine dura. We then used Fgfr2 inhibitors to knock down the expression of Fgfr2 mRNA in an MC3T3 osteoblast cell line and found changes in gene expression of some, but not all, putative target genes, linking the expression levels of these genes to FGFR2 signalling. This study identifies five genes previously associated with osteogenesis, that are implicated as downstream regulators of coronal suture fusion in human FGFR2 syndromes.


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