Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice

BMC Developmental Biology

Joan T Richtsmeier⁴  Ethylin Wang Jabs⁵  Kristina Aldridge⁶  Neus Martínez-Abadías¹  Theodore M Cole²  Susan M Motch Perrine³ 

[1] Current address: CRG, Center for Genomic Regulation, Dr. Aiguader, 88, 08003 Barcelona, Spain;Department of Basic Medical Science, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64110, USA;Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA;Center for Functional Anatomy and Evolution, Johns Hopkins University School of Medicine, Baltimore, MD 21228, USA;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, USA

关键词: Apert syndrome;    Craniosynostosis;    Suture;    Skull growth;    Cranial development;    Fibroblast growth factor receptor signaling;   

Others  :  1160956
DOI  :  10.1186/1471-213X-14-8

 received in 2013-11-18, accepted in 2014-02-05,  发布年份 2014

【 摘 要 】

Background

Differences 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.

Results

We 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.

Conclusions

Our 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.

【 授权许可】

   
2014 Motch Perrine et al.; licensee BioMed Central Ltd.

【 图 表 】

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