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

Abstract

Background The role of fibroblast growth factor and receptor (FGF/FGFR) signaling in bone development is well studied, partly because mutations in FGFRs cause human diseases of achondroplasia and FGFR-related craniosynostosis syndromes including Crouzon syndrome. The FGFR2c C342Y mutation is a frequent cause of Crouzon syndrome, characterized by premature cranial vault suture closure, midfacial deficiency and neurocranial dysmorphology. Here, using newborn Fgfr2cC342Y/+ Crouzon syndrome mice, we tested whether the phenotypic effects of this mutation go beyond the skeletal tissues of the skull, altering the development of other non-skeletal head tissues including the brain, the eyes, the nasopharynx and the inner ears. Results Quantitative analysis of 3D multimodal imaging (high resolution micro computed tomography and magnetic resonance microscopic images) revealed local differences in skull morphology and coronal suture patency between Fgfr2cC342Y/+ mice and unaffected littermates, as well as changes in brain shape but not brain size, significant reductions in nasopharyngeal and eye volumes, and no difference in inner ear volume in Fgfr2cC342Y/+ mice. Conclusion These findings provide an expanded catalogue of clinical phenotypes in Crouzon syndrome caused by aberrant FGF/FGFR signaling and evidence of the broad role for FGF/FGFR signaling in development and evolution of the vertebrate head.

Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses

“…In animal models for human craniosynostosis syndromes, the abnormal skull shape can be detected before the premature closure of cranial vault sutures 71•, 72•]. The development of animal models for craniosynostosis [70, 73, 74] has already revealed many molecularly driven three-dimensional morphological changes in soft tissues of the head and skull that were not apparent in humans [71•, 75, 76•, 77]. These changes are more difficult to evaluate quantitatively in humans where observations are routinely made postnatally and there is a lack of appropriate morphological control data sets to make meaningful comparisons to abnormal phenotypes.…”

From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome

“…FGF/FGFR signaling is known to be complex, and tissue-specific responses are widespread and variable (Wilke et al, 1997; Ornitz and Marie, 2002; Dorey and Amaya, 2010; Hébert, 2011; Martínez-Abadías et al, 2011; Martínez-Abadías et al, 2013). The identity of FGFs expressed during early craniofacial morphogenesis and palatal formation have been extensively characterized (Britto et al, 2002; Bachler and Neubüser, 2001; Welsh et al, 2007), but the complement of FGFs expressed in the facial sutures during late embryological development is undefined.…”

Foramen Magnum Size and Involvement of Its Intraoccipital Synchondroses in Crouzon Syndrome

“…[24][25][26][27] Several studies reported abnormalities of the skull 2,5,9,28,29 and skull base 9,13,30 in Crouzon syndrome in humans and in mice. [31][32][33] Thus, it is likely that FGFR2 gene mutations have an effect on hindbrain development and give rise to abnormal growth of its surrounding bone plates (i.e., the foramen magnum). Although there are various publications concerning the cranial base in mice and humans, little has been written about the cranial base in Crouzon patients, not to mention about the intraoccipital synchondroses in these patients.…”