Peskett, E;
Kumar, S;
Baird, W;
Jaiswal, J;
Li, M;
Patel, P;
Britto, JA;
(2017)
Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme.
Biol Open
10.1242/bio.022178.
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Abstract
Syndromic craniosynostosis caused by mutations in FGFR2 is characterised by developmental pathology in both endochondral and membranous skeletogenesis. Detailed phenotypic characterisation of features in the membranous calvarium, the endochondral cranial base and other structures in the axial and appendicular skeleton has not been performed at embryonic stages. We investigated bone development in the Crouzon mouse model (Fgfr2(C342Y)) at pre- and post-ossification stages to improve understanding of the underlying pathogenesis.Phenotypic analysis was performed by whole mount skeletal staining (Alcian Blue/Alizarin Red) and histological staining of sections of CD1 wild-type (WT), Fgfr2(C342Y/+) heterozygous (HET) and Fgfr2(C342Y/C342Y) homozygous (HOM) mouse embryos from E12.5-E17.5 stages. Gene expression (Sox9, Shh, Fgf10, and Runx2) was studied by in situ hybridisation and protein expression (COL2A1) by immunohistochemistry.Our analysis has identified severely decreased osteogenesis in parts of the craniofacial skeleton together with increased chondrogenesis in parts of the endochondral and cartilaginous skeleton in HOM embryos. The Sox9 expression domain in tracheal and basi-cranial chondrocytic precursors at E13.5 in HOM embryos is increased and expanded, correlating with the phenotypic observations which suggests FGFR2 signalling regulates Sox9 expression. Combined with abnormal staining of type II collagen in pre-chondrocytic mesenchyme, this is indicative of a mesenchymal condensation defect.An expanded spectrum of phenotypic features observed in the Fgfr2(C342Y/C342Y) mouse embryo paves the way towards better understanding the clinical attributes of human Crouzon-Pfeiffer syndrome. FGFR2 mutation results in impaired skeletogenesis, however our findings suggest that many phenotypic aberrations stem from a primary failure of pre-chondrogenic/osteogenic mesenchymal condensation and links FGFR2 to SOX9, a principal regulator of skeletogenesis.
| Type: | Article |
|---|---|
| Title: | Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme. |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/bio.022178 |
| Publisher version: | http://dx.doi.org/10.1242/bio.022178 |
| Additional information: | © 2017. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| Keywords: | Crouzon, FGFR2, RUNX2, SOX9, craniosynostosis, mesenchyme |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1535958 |
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