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Dis Model Mech. 2018 Sep 28. pii: dmm.035311. doi: 10.1242/dmm.035311. [Epub ahead of print]

Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse.

Author information

1
Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
2
Genetics & Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
3
ICH GOSH Light Microscopy Core Facility, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
4
Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK e.pauws@ucl.ac.uk.

Abstract

FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative for multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that both the activation (Fgfr2c C342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2c null) of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression.Conditional overexpression of Fgfr2c (R26R Fgfr2c;βact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2c null and Fgfr2c C342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2c C342Y and R26R Fgfr2c;βact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2c C342Y and R26R Fgfr2c;βact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2c C342Y), in particular to the coronal suture. Our results demonstrate that Fgfr2c overexpression is sufficient to partially rescue craniosynostosis through increased proliferation and reduced osteogenic activity in E18.5 Fgfr2c C342Y embryos.This study demonstrates the intricate balance of FGF signalling required for correct calvarial bone and suture morphogenesis, and that increasing the expression of the wild-type FGFR2c isoform may be a way to prevent or delay craniosynostosis progression.

KEYWORDS:

Cleft palate; Craniosynostosis; Crouzon; ERK; FGF; FGFR2

PMID:
30266836
DOI:
10.1242/dmm.035311
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