Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos
Human mutations in the planar cell polarity component VANGL2 are associated with the neural tube defect spina bifida. Homozygous Vangl2 mutation in mice prevents initiation of neural tube closure, precluding analysis of its subsequent roles in neurulation. Spinal neurulation involves rostral-to-caud...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2018-03-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/11/3/dmm032219 |
| _version_ | 1818864015424618496 |
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| author | Gabriel L. Galea Oleksandr Nychyk Matteo A. Mole Dale Moulding Dawn Savery Evanthia Nikolopoulou Deborah J. Henderson Nicholas D. E. Greene Andrew J. Copp |
| author_facet | Gabriel L. Galea Oleksandr Nychyk Matteo A. Mole Dale Moulding Dawn Savery Evanthia Nikolopoulou Deborah J. Henderson Nicholas D. E. Greene Andrew J. Copp |
| author_sort | Gabriel L. Galea |
| collection | DOAJ |
| description | Human mutations in the planar cell polarity component VANGL2 are associated with the neural tube defect spina bifida. Homozygous Vangl2 mutation in mice prevents initiation of neural tube closure, precluding analysis of its subsequent roles in neurulation. Spinal neurulation involves rostral-to-caudal ‘zippering’ until completion of closure is imminent, when a caudal-to-rostral closure point, ‘Closure 5’, arises at the caudal-most extremity of the posterior neuropore (PNP). Here, we used Grhl3Cre to delete Vangl2 in the surface ectoderm (SE) throughout neurulation and in an increasing proportion of PNP neuroepithelial cells at late neurulation stages. This deletion impaired PNP closure after the ∼25-somite stage and resulted in caudal spina bifida in 67% of Grhl3Cre/+Vangl2Fl/Fl embryos. In the dorsal SE, Vangl2 deletion diminished rostrocaudal cell body orientation, but not directional polarisation of cell divisions. In the PNP, Vangl2 disruption diminished mediolateral polarisation of apical neuroepithelial F-actin profiles and resulted in eversion of the caudal PNP. This eversion prevented elevation of the caudal PNP neural folds, which in control embryos is associated with formation of Closure 5 around the 25-somite stage. Closure 5 formation in control embryos is associated with a reduction in mechanical stress withstood at the main zippering point, as inferred from the magnitude of neural fold separation following zippering point laser ablation. This stress accommodation did not happen in Vangl2-disrupted embryos. Thus, disruption of Vangl2-dependent planar-polarised processes in the PNP neuroepithelium and SE preclude zippering point biomechanical accommodation associated with Closure 5 formation at the completion of PNP closure. |
| first_indexed | 2024-12-19T10:24:56Z |
| format | Article |
| id | doaj.art-73ca39b5577f4172b3706a326f3894fd |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-19T10:24:56Z |
| publishDate | 2018-03-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-73ca39b5577f4172b3706a326f3894fd2022-12-21T20:25:57ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-03-0111310.1242/dmm.032219032219Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryosGabriel L. Galea0Oleksandr Nychyk1Matteo A. Mole2Dale Moulding3Dawn Savery4Evanthia Nikolopoulou5Deborah J. Henderson6Nicholas D. E. Greene7Andrew J. Copp8 Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Developmental Biology of Birth Defects, UCL GOS Institute of Child Health, London, WC1N 1EH, UK Human mutations in the planar cell polarity component VANGL2 are associated with the neural tube defect spina bifida. Homozygous Vangl2 mutation in mice prevents initiation of neural tube closure, precluding analysis of its subsequent roles in neurulation. Spinal neurulation involves rostral-to-caudal ‘zippering’ until completion of closure is imminent, when a caudal-to-rostral closure point, ‘Closure 5’, arises at the caudal-most extremity of the posterior neuropore (PNP). Here, we used Grhl3Cre to delete Vangl2 in the surface ectoderm (SE) throughout neurulation and in an increasing proportion of PNP neuroepithelial cells at late neurulation stages. This deletion impaired PNP closure after the ∼25-somite stage and resulted in caudal spina bifida in 67% of Grhl3Cre/+Vangl2Fl/Fl embryos. In the dorsal SE, Vangl2 deletion diminished rostrocaudal cell body orientation, but not directional polarisation of cell divisions. In the PNP, Vangl2 disruption diminished mediolateral polarisation of apical neuroepithelial F-actin profiles and resulted in eversion of the caudal PNP. This eversion prevented elevation of the caudal PNP neural folds, which in control embryos is associated with formation of Closure 5 around the 25-somite stage. Closure 5 formation in control embryos is associated with a reduction in mechanical stress withstood at the main zippering point, as inferred from the magnitude of neural fold separation following zippering point laser ablation. This stress accommodation did not happen in Vangl2-disrupted embryos. Thus, disruption of Vangl2-dependent planar-polarised processes in the PNP neuroepithelium and SE preclude zippering point biomechanical accommodation associated with Closure 5 formation at the completion of PNP closure.http://dmm.biologists.org/content/11/3/dmm032219Neural tubeVangl2BiomechanicsF-actinMouseEmbryo |
| spellingShingle | Gabriel L. Galea Oleksandr Nychyk Matteo A. Mole Dale Moulding Dawn Savery Evanthia Nikolopoulou Deborah J. Henderson Nicholas D. E. Greene Andrew J. Copp Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos Disease Models & Mechanisms Neural tube Vangl2 Biomechanics F-actin Mouse Embryo |
| title | Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| title_full | Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| title_fullStr | Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| title_full_unstemmed | Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| title_short | Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| title_sort | vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| topic | Neural tube Vangl2 Biomechanics F-actin Mouse Embryo |
| url | http://dmm.biologists.org/content/11/3/dmm032219 |
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