Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse
FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative of multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that the activation (Fgfr2cC342Y; a mouse model for human Crouzon syn...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2018-11-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/11/11/dmm035311 |
| _version_ | 1811234569308864512 |
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| author | Kevin K. L. Lee Emma Peskett Charlotte M. Quinn Rosanna Aiello Liliya Adeeva Dale A. Moulding Philip Stanier Erwin Pauws |
| author_facet | Kevin K. L. Lee Emma Peskett Charlotte M. Quinn Rosanna Aiello Liliya Adeeva Dale A. Moulding Philip Stanier Erwin Pauws |
| author_sort | Kevin K. L. Lee |
| collection | DOAJ |
| description | FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative of multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that the activation (Fgfr2cC342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2cnull), 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 (R26RFgfr2c;βact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2cnull and Fgfr2cC342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2cC342Y and R26RFgfr2c;βact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2cC342Y and R26RFgfr2c;βact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2cC342Y), in particular its effects on 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 Fgfr2cC342Y 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 could be a way to prevent or delay craniosynostosis progression. |
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| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T11:38:31Z |
| publishDate | 2018-11-01 |
| publisher | The Company of Biologists |
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| series | Disease Models & Mechanisms |
| spelling | doaj.art-533c7c94dcf5409d880d7aa80046e4de2022-12-22T03:34:44ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-11-01111110.1242/dmm.035311035311Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouseKevin K. L. Lee0Emma Peskett1Charlotte M. Quinn2Rosanna Aiello3Liliya Adeeva4Dale A. Moulding5Philip Stanier6Erwin Pauws7 Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK ICH GOSH Light Microscopy Core Facility, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative of multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that the activation (Fgfr2cC342Y; a mouse model for human Crouzon syndrome), as well as the removal (Fgfr2cnull), 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 (R26RFgfr2c;βact) results in craniofacial hypoplasia as well as microtia and cleft palate. Contrary to Fgfr2cnull and Fgfr2cC342Y, Fgfr2c overexpression is insufficient to drive onset of craniosynostosis. Examination of the MAPK/ERK pathway in the embryonic sutures of Fgfr2cC342Y and R26RFgfr2c;βact mice reveals that both mutants have increased pERK expression. The contrasting phenotypes between Fgfr2cC342Y and R26RFgfr2c;βact mice prompted us to assess the impact of the Fgfr2c overexpression allele on the Crouzon mouse (Fgfr2cC342Y), in particular its effects on 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 Fgfr2cC342Y 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 could be a way to prevent or delay craniosynostosis progression.http://dmm.biologists.org/content/11/11/dmm035311FGFR2FGFCraniosynostosisCleft palateCrouzonERK |
| spellingShingle | Kevin K. L. Lee Emma Peskett Charlotte M. Quinn Rosanna Aiello Liliya Adeeva Dale A. Moulding Philip Stanier Erwin Pauws Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse Disease Models & Mechanisms FGFR2 FGF Craniosynostosis Cleft palate Crouzon ERK |
| title | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse |
| title_full | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse |
| title_fullStr | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse |
| title_full_unstemmed | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse |
| title_short | Overexpression of Fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the Crouzon mouse |
| title_sort | overexpression of fgfr2c causes craniofacial bone hypoplasia and ameliorates craniosynostosis in the crouzon mouse |
| topic | FGFR2 FGF Craniosynostosis Cleft palate Crouzon ERK |
| url | http://dmm.biologists.org/content/11/11/dmm035311 |
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