title: Activating (P253R, C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation, differentiation, and mineralization.
abstract: Various activating mutations of FgfR2 have been linked to a number of craniosynostosis syndromes, suggesting that FGFR2-mediated signaling plays significant roles in intramembranous bone formation. To define (i) the roles of FGFR2-mediated signaling in osteogenesis and (ii) bone cell functions affected by abnormal signaling induced by craniosynostosis mutations, chicken calvarial osteoblasts were infected with replication competent avian sarcoma viruses expressing FgfR2 with dominant negative (DN), P253R (Apert), or C278F (Pfeiffer and Crouzon) mutation. Analyses of the infected osteoblasts revealed that attenuated FGF/FGFR signaling by DN-FgfR2 resulted in a decrease in cell proliferation and accelerated mineralization. In contrast, the C278F mutation, which causes ligand-independent activation of the receptor, significantly stimulated cell proliferation and inhibited mineralization. Interestingly, the P253R mutation, which does not cause ligand-independent activation of the receptor, showed a weaker mitogenic effect than the C278F mutation and did not inhibit mineralization. Gene expression analysis also revealed diverse effects of C278F and P253R mutations on expression of several osteogenic genes. Based on these results, we conclude that one of the major functions of FGFR2 is to mediate mitogenic signals in osteoblasts and that distinctively different cellular mechanisms underlie the pathogenesis of craniosynostosis phenotypes resulting from P253R and C278F mutations of the FGFR2 gene.
authors.affiliation: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Chootima
authors.initials: C
authors.lastname: Ratisoontorn
authors.forename: Gao-Feng
authors.initials: GF
authors.lastname: Fan
authors.forename: Kerry
authors.initials: K
authors.lastname: McEntee
authors.forename: Hyun-Duck
authors.initials: HD
authors.lastname: Nah
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000235:genetics*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002642:Chick Embryo; D003001:Cloning, Molecular; D005799:Genes, Dominant / Q000235:genetics*; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D014162:Transfection
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2