A craniosynostosis‐syndrome related Fgfr2 mutation promotes early craniofacial defects in chick

Abstract

In addition to premature suture closure, patients with craniosynostosis have a variety of structural deformities in the brain and face. Whether brain and face malformations result from premature suture closure, or are caused directly by disease‐causing mutations are unknown. Gain‐of‐function mutations in Fibroblast Growth Factor Receptors (FGFRs) account for ~20% of craniosynostosis syndromes, and mice harboring a ubiquitously expressed, disease‐causing allele of FGFR2 recapitulate craniosynostosis phenotypes. To test the hypothesis that facial malformations result directly from activation of FGFR2 in the face, we introduced the human Fgfr2C278F mutant allele into chick embryos using the RCAS virus. RCAS::Fgfr2C278F particles were injected into mesenchyme adjacent to the forebrain after neural crest emigration form the neural tube was complete (stage 10). After 72 hrs embryos were harvested for analysis. Infected embryos were microcephalic, appeared to have widened faces, and had more prominent and hypertrophic nasal pits compared to controls. Consistent with FGF activation, we observed increased pErk staining. Infected embryos also had fewer proliferating cells. In conclusion, our results demonstrate that activation of the FGF pathway produces dysmorphology independent of premature suture fusion that resembles the facial phenotype of people with craniosynostosis.Grant Funding Source: NIH