Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice

Abstract

BackgroundDifferences in cranial morphology arise due to changes in fundamental cell processes like migration, proliferation, differentiation and cell death driven by genetic programs. Signaling between fibroblast growth factors (FGFs) and their receptors (FGFRs) affect these processes during head development and mutations in FGFRs result in congenital diseases including FGFR-related craniosynostosis syndromes. Current research in model organisms focuses primarily on how these mutations change cell function local to sutures under the hypothesis that prematurely closing cranial sutures contribute to skull dysmorphogenesis. Though these studies have provided fundamentally important information contributing to the understanding of craniosynostosis conditions, knowledge of changes in cell function local to the sutures leave change in overall three-dimensional cranial morphology largely unexplained. Here we investigate growth of the skull in two inbred mouse models each carrying one of two gain-of-function mutations in FGFR2 on neighboring amino acids (S252W and P253R) that in humans cause Apert syndrome, one of the most severe FGFR-related craniosynostosis syndromes. We examine late embryonic skull development and suture patency in Fgfr2 Apert syndrome mice between embryonic day 17.5 and birth and quantify the effects of these mutations on 3D skull morphology, suture patency and growth.ResultsWe show in mice what studies in humans can only infer: specific cranial growth deviations occur prenatally and worsen with time in organisms carrying these FGFR2 mutations. We demonstrate that: 1) distinct skull morphologies of each mutation group are established by E17.5; 2) cranial suture patency patterns differ between mice carrying these mutations and their unaffected littermates; 3) the prenatal skull grows differently in each mutation group; and 4) unique Fgfr2-related cranial morphologies are exacerbated by late embryonic growth patterns.ConclusionsOur analysis of mutation-driven changes in cranial growth provides a previously missing piece of knowledge necessary for explaining variation in emergent cranial morphologies and may ultimately be helpful in managing human cases carrying these same mutations. This information is critical to the understanding of craniofacial development, disease and evolution and may contribute to the evaluation of incipient therapeutic strategies.

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.…”

Fibroblast growth factor signaling in skeletal development and disease

“…Genetic, cellular, and molecular studies in mice and humans provided clues to the abnormalities induced by gain-of-function FGFR mutations (Hajihosseini 2008;Marie et al 2008;SenarathYapa et al 2012). Specifically, Apert FGFR2(S252W) mutations were shown to induce abnormal mesodermal progenitor cell proliferation, differentiation, and cell fate in cranial sutures in various mouse models, although the cellular abnormalities vary among specific sutures and between cells at distinct stages of differentiation in a particular suture Holmes et al 2009;Heuze et al 2014;Motch Perrine et al 2014).…”

Integration of comprehensive 3D microCT and signaling analysis reveals differential regulatory mechanisms of craniofacial bone development

“…Studies are now using different mouse models along with 3D microCT to analyze different stages of craniofacial bone development, for example, in Apert Syndrome mice (Perrine et al, 2014; Percival et al, 2014). However, the underlying mechanisms of craniofacial bone development remain to be elucidated.…”

“…We did not observe a significant change in volume in the occipital bone (control: 0.297mm 3 ±0.069; R2 CKO: 0.236mm 3 ±0.052; p=0.1432). Previous studies have shown that the developmental processes of craniofacial bones with different origin are interrelated (Perrine et al, 2014; Percival et al, 2014; Yoshida et al, 2008). Therefore, the effects on the parietal bone, interparietal bone and other non-CNC-derived craniofacial bones may be secondary.…”