Lee, King Lam;
(2018)
Exploring The Role Of FGFR2c Misregulation In Syndromic Craniosynostosis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Craniosynostosis is a common feature of craniofacial birth defects, and is characterised by premature fusion of the cranial sutures in the developing calvarium. Pathogenic FGFR2 signalling is a major cause of syndromic craniosynostosis and is caused by activating mutations within the FGFR2 gene. In particular, mutations affecting the IIIc isoform (i.e. FGFR2c-C342Y) contribute to coronal synostosis, a common phenotype in human Crouzon syndrome. This study aims to address the downstream effects of misregulated FGFR2c signalling in vivo. Conditional overexpression of Fgfr2c (R26RFgfr2cV5/+; βactinCRE/+) results in craniofacial hypoplasia without coronal synostosis, which is in contrast to Fgfr2cC342Y/+, a well-studied mouse model for human Crouzon syndrome. Assessment of the coronal suture reveals that R26RFgfr2cV5/+; βactinCRE/+ and Fgfr2cC342Y/+ have opposing phenotypes, where the former display insufficient osteoblast activity. However, biochemical examination of RAS-MAPK activity in embryonic sutures of Fgfr2cC342Y/+ and R26RFgfr2cV5/+; βactinCRE/+ demonstrates upregulated pERK expression. The opposing phenotypes seen between Fgfr2cC342Y/+ and R26RFgfr2cV5/+; βactinCRE/+ mice suggested the possibility that Fgfr2c overexpression on the Fgfr2cC342Y/+ (R26RFgfr2cV5/+;βactinCRE/+;Fgfr2cC342Y/+) genotype may serve to ameliorate the Crouzon phenotype. This study reports that the Crouzon phenotype was only partly spared in R26RFgfr2cV5/+;βactinCRE/+;Fgfr2cC342Y/+ mice, together with a partial rescue of the coronal suture. The latter was due to delayed calvarial ossification as well as reduced osteoblast activity. Therefore, this study demonstrated that an intricate balance would be required for FGF signalling in order to correct calvarial bone and suture morphogenesis, and that increasing the expression of the wild-type FGFR2c isoform may be a viable method to prevent or delay craniosynostosis progression. In addition, this study has uncovered a novel role for cartilage in craniosynostosis development and has performed comparative expression-profiling (RNAseq) on the E16.5 coronal suture of Fgfr2cC342Y/+ and WTs to uncover novel genes potentially involved in syndromic craniosynostosis. Further elucidation of the highly complex FGFR2c signalling pathway remains to be deciphered in order to improve our understanding of normal craniofacial development and its related pathologies, while providing a framework for the innovation of novel therapeutic strategies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Exploring The Role Of FGFR2c Misregulation In Syndromic Craniosynostosis |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10062366 |
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