Tissue-specific responses to aberrant FGF signaling in complex head phenotypes

Area of Science:

• Developmental Biology
• Genetics
• Craniofacial Biology

Background:

• Fibroblast growth factor and receptor (FGF/FGFR) signaling is crucial for bone development.
• Mutations in FGFRs cause skeletal disorders like achondroplasia and Crouzon syndrome.
• The FGFR2c C342Y mutation is a common cause of Crouzon syndrome, characterized by craniosynostosis and midfacial deficiency.

Purpose of the Study:

• To investigate the non-skeletal phenotypic effects of the FGFR2c C342Y mutation in Crouzon syndrome.
• To determine if the mutation impacts the development of the brain, eyes, nasopharynx, and inner ears.
• To expand the understanding of FGF/FGFR signaling's role in craniofacial development.

Main Methods:

• Utilized newborn Fgfr2c(C342Y/+) Crouzon syndrome mouse models.
• Employed quantitative analysis of 3D multimodal imaging, including high-resolution micro-computed tomography and magnetic resonance microscopy.
• Compared craniofacial and non-skeletal head tissue development between mutant mice and unaffected littermates.

Main Results:

• Observed local differences in skull morphology and coronal suture patency in mutant mice.
• Detected changes in brain shape, but not overall brain size.
• Found significant reductions in nasopharyngeal and eye volumes in Fgfr2c(C342Y/+) mice.
• No significant difference in inner ear volume was noted between groups.

Conclusions:

• The FGFR2c C342Y mutation in Crouzon syndrome leads to a broader spectrum of phenotypes beyond skeletal abnormalities.
• Aberrant FGF/FGFR signaling has a significant impact on the development of multiple non-skeletal head tissues.
• These findings underscore the extensive role of FGF/FGFR signaling in vertebrate head development and evolution.