Date of Award
Medical Doctor (MD)
Derek M. Steinbacher
Developmental biology, Surgery, Cellular biology
Mitigation of Shp2 and Grb2 Activation Prevents Fibroblast Growth Factor Receptor 2 Signaling-Induced Craniosynostosis Through an ERK1/2-Dependent Pathway
Miles J. Pfaff1, Derek M. Steinbacher2, and Veraragavan P. Eswarakumar3
1. Yale University School of Medicine
2. Section of Plastic and Reconstructive Surgery, Dept. of Surgery, Yale University School of Medicine
3. Dept. of Orthopaedics and Rehabilitation and of Pharmacology
Introduction: 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 is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to neural and craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The docking protein, FRS2α, is a known mediator of FGFR2c signaling that interacts with Shp2, a tyrosine phosphatase, and Grb2, an adapter protein, to positively regulate ERK-MAPK signaling. The aim of this study is to investigate the role FRS2α-mediated Shp2 and Grb2 activation in the development of craniosynostosis in a mouse model of Crouzon syndrome.
Methods: Mutations resulting in loss- and gain-of-function of Fgfr2c and mutations resulting in loss of FRS2α-mediated Shp2 and Grb2 activation were analyzed in mice to understand the regulatory processes leading to craniosynostosis and craniofacial maldevelopment. Results: Loss- and gain-of-function Fgfr2c mutant mice revealed overlapping disease manifestations including coronal synostosis as a consequence of dyregulated osteoblast function that was mediated through an ERK-MAPK-dependent signaling mechanism. Selective uncoupling of FRS2α with Shp2 or with Grb2 prevented craniosynostosis and restored normal craniofacial development and osteoblast function in Crouzon-like mice by modulating ERK-MAPK signaling.
Conclusion: This study illustrates a novel pathogenic role for FRS2α-mediate Shp2 and Grb2 activation in the setting of dysregulated FGFR2c signaling and highlights the therapeutic potential of inhibition of these signaling mediators for the treatment of craniosynostosis and other skeletal disorders.
Pfaff, Miles Jackson, "Mitigation Of Shp2 And Grb2 Activation Prevents Fibroblast Growth Factor Receptor 2 Signaling-Induced Craniosynostosis Through An Erk1/2-Dependent Pathway" (2014). Yale Medicine Thesis Digital Library. 1915.