title: Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology.
abstract: Activating mutations of FGFRs1-3 cause craniosynostosis (CS), the premature fusion of cranial bones, in man and mouse. The mechanisms by which such mutations lead to CS have been variously ascribed to increased osteoblast proliferation, differentiation, and apoptosis, but it is not always clear how these disturbances relate to the process of suture fusion. We have reassessed coronal suture fusion in an Apert Fgfr2 (S252W) mouse model. We find that the critical event of CS is the early loss of basal sutural mesenchyme as the osteogenic fronts, expressing activated Fgfr2, unite to form a contiguous skeletogenic membrane. A mild increase in osteoprogenitor proliferation precedes but does not accompany this event, and apoptosis is insignificant. On the other hand, the more apical coronal suture initially forms appropriately but then undergoes fusion, albeit at a slower rate, accompanied by a significant decrease in osteoprogenitor proliferation, and increased osteoblast maturation. Apoptosis now accompanies fusion, but is restricted to bone fronts in contact with one another. We correlated these in vivo observations with the intrinsic effects of the activated Fgfr2 S252W mutation in primary osteoblasts in culture, which show an increased capacity for both proliferation and differentiation. Our studies suggest that the major determinant of Fgfr2-induced craniosynostosis is the failure to respond to signals that would halt the recruitment or the advancement of osteoprogenitor cells at the sites where sutures should normally form.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Holmes
authors.forename: Gerson
authors.initials: G
authors.lastname: Rothschild
authors.forename: Upal Basu
authors.initials: UB
authors.lastname: Roy
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Alka
authors.initials: A
authors.lastname: Mansukhani
authors.forename: Claudio
authors.initials: C
authors.lastname: Basilico
mesh_terms: D000168:Acrocephalosyndactylia / Q000196:embryology / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003398:Craniosynostoses / Q000196:embryology* / Q000235:genetics / Q000473:pathology; D008648:Mesoderm / Q000166:cytology / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000473:pathology* / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000473:pathology* / Q000502:physiology
chemical_list: C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2