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Updated: Jul 18, 2026
Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis
Published on: April 1, 2022
Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents
V P Eswarakumar1, F Ozcan, E D Lew
1Department of Pharmacology and Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Abstract:
Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, approximately 20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). We describe a genetic and pharmacological approach for the treatment of a murine model system of Crouzon-like craniosynostosis induced by a dominant mutation in Fgfr2c. Using genetically modified mice, we demonstrate that premature fusion of sutures mediated by Crouzon-like activated Fgfr2c mutant is prevented by attenuation of signaling pathways by selective uncoupling between the docking protein Frs2alpha and activated Fgfr2c, resulting in normal skull development. We also demonstrate that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevents premature fusion of sutures without adversely affecting calvaria development. These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment.
Insights
Craniosynostosis, a skull fusion disorder, can be treated by targeting FGF signaling pathways. This study shows that inhibiting FGFR signaling in mice prevents premature skull fusion, offering hope for new therapies.
Area of Science:
- Genetics
- Pharmacology
- Developmental Biology
Background:
- Craniosynostosis is a common birth defect caused by premature skull suture fusion.
- Gain-of-function mutations in Fibroblast Growth Factor Receptors (FGFRs) cause approximately 20% of craniosynostosis cases.
- Current treatments for craniosynostosis are limited, especially for FGFR-related conditions.
Purpose of the Study:
- To investigate a genetic and pharmacological approach for treating Crouzon-like craniosynostosis in a mouse model.
- To determine if attenuating FGFR signaling can prevent premature suture fusion.
- To assess the safety and efficacy of FGFR inhibition on skull development.
Main Methods:
- Utilized genetically modified mice with a dominant mutation in Fgfr2c to model Crouzon-like craniosynostosis.
- Investigated the effect of selectively uncoupling Frs2alpha from activated Fgfr2c on suture development.
- Employed an FGFR inhibitor in calvaria organ cultures to assess its impact on suture fusion and development.
Main Results:
- Genetic modification preventing Frs2alpha-Fgfr2c coupling normalized skull development in the mouse model.
- FGFR inhibition in organ cultures prevented premature suture fusion without adverse effects on calvaria development.
- Demonstrated that attenuation of FGFR signaling effectively prevents craniosynostosis in experimental models.
Conclusions:
- Attenuation of FGFR signaling, through genetic or pharmacological means, can prevent craniosynostosis.
- Pharmacological intervention targeting FGFR signaling presents a potential therapeutic strategy for craniosynostosis and other severe bone disorders.
- This research opens avenues for novel treatments for FGFR-mutation-related skeletal abnormalities.
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