title: FGFR2c-mediated ERK-MAPK activity regulates coronal suture development.
abstract: Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor's gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis.
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Miles J
authors.initials: MJ
authors.lastname: Pfaff
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States; Department of Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xue
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Horowitz
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Steinbacher
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States. Electronic address: Jacob.Eswarakumar@yale.edu.
authors.forename: Jacob V P
authors.initials: JVP
authors.lastname: Eswarakumar
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003393:Cranial Sutures / Q000002:abnormalities / Q000196:embryology*; D003394:Craniofacial Dysostosis / Q000196:embryology*; D004789:Enzyme Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D010641:Phenotype; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013580:Synostosis / Q000235:genetics / Q000473:pathology
chemical_list: D002070:Butadienes; D009570:Nitriles; D020033:Protein Isoforms; C113580:U 0126; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000469:Alkaline Phosphatase
keywords: Coronal suture; Craniosynostosis; Crouzon syndrome; ERK–MAPK; FGF; FGFR2