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FGFR2c-mediated ERK-MAPK activity regulates coronal suture development.
Dev Biol. 2016 07 15; 415(2):242-250.DB

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+Show Affiliations

Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States.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.Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States.Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, United States.Department of Surgery, Yale University School of Medicine, New Haven, CT, United States.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27034231

Citation

Pfaff, Miles J., et al. "FGFR2c-mediated ERK-MAPK Activity Regulates Coronal Suture Development." Developmental Biology, vol. 415, no. 2, 2016, pp. 242-250.
Pfaff MJ, Xue K, Li L, et al. FGFR2c-mediated ERK-MAPK activity regulates coronal suture development. Dev Biol. 2016;415(2):242-250.
Pfaff, M. J., Xue, K., Li, L., Horowitz, M. C., Steinbacher, D. M., & Eswarakumar, J. V. P. (2016). FGFR2c-mediated ERK-MAPK activity regulates coronal suture development. Developmental Biology, 415(2), 242-250. https://doi.org/10.1016/j.ydbio.2016.03.026
Pfaff MJ, et al. FGFR2c-mediated ERK-MAPK Activity Regulates Coronal Suture Development. Dev Biol. 2016 07 15;415(2):242-250. PubMed PMID: 27034231.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FGFR2c-mediated ERK-MAPK activity regulates coronal suture development. AU - Pfaff,Miles J, AU - Xue,Ke, AU - Li,Li, AU - Horowitz,Mark C, AU - Steinbacher,Derek M, AU - Eswarakumar,Jacob V P, Y1 - 2016/03/28/ PY - 2015/07/01/received PY - 2016/03/25/revised PY - 2016/03/25/accepted PY - 2016/4/2/entrez PY - 2016/4/2/pubmed PY - 2017/6/27/medline KW - Coronal suture KW - Craniosynostosis KW - Crouzon syndrome KW - ERK–MAPK KW - FGF KW - FGFR2 SP - 242 EP - 250 JF - Developmental biology JO - Dev. Biol. VL - 415 IS - 2 N2 - 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. SN - 1095-564X UR - https://www.unboundmedicine.com/medline/citation/27034231/FGFR2c_mediated_ERK_MAPK_activity_regulates_coronal_suture_development_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(16)30155-5 DB - PRIME DP - Unbound Medicine ER -