Molecularbiological study of craniofacial dysmorphology in transgenic mice bearing Apert type mutant Fgfr2 gene

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To test a hypothesis that the cartilage is another target for the mutant FGFR2 signaling, we generated transgenic mice expressing Fgfr2 IIIc bearing Apert syndrome type mutation (Fgfr2 IIIc^<P253R>) selectively in chondrocytes. These mice markedly manifested deformities of the cranium including premature fusion of cartilaginous sutures in the cranial base(synchondroses), which accompanied by domed skull with wide opened metopic suture, maxillary hypoplasia, and shortening of anterior cranial base. As a likely cause of the prominent cranial deformities, we hypothesized specific expression patterns of FGF ligands that could produce aberrant FGFR2 signaling in cranial cartilage. The results of gene expression analyses by Lasermicrodisection(LMD)/Real time PCR(R-PCR) and organ culture system with FGFs stimulation demonstrated the acquirement of edopic autocrine regulation by Fgfi2 IIIc^<P253R> expression in concert with the specific distribution pattern of FGF2 and FGF10 ligand in cranial base cartilage. These results propose importance role of abnormal development of the cranial base cartilage as another basic mechanism of the preferential craniofacial dysmorphologies in Apert syndrome. To clarify the biological effect of activation of FGFR2 signaling, we used the LMD/R-PCR system to analyze the differentiation markers for chondrocyte lineage cells. Consistent with histological findings, LMD/R-PCR data have suggested activation of the molecules, Cbfa1, Ihh and MMP-13,which are involved in hypertrophic differentiation of the chondrocyte. Taken together, aberrant activation of FGFR2 signaling in cranial cartilage could result acceleration of chondrocyte terminal differentiation, consequently, resulting the craniofacial dysmorphology with premature fusion of cranial synchondroses.