Galea, GL;
Nychyk, O;
Mole, MA;
Moulding, D;
Savery, D;
Nikolopoulou, E;
Henderson, DJ;
... Copp, AJ; + view all
(2018)
Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos.
Disease Models & Mechanisms
, 11
(3)
, Article dmm032219. 10.1242/dmm.032219.
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Abstract
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 usedGrhl3Creto 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% ofGrhl3Cre/+Vangl2Fl/Flembryos. 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.
| Type: | Article |
|---|---|
| Title: | Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/dmm.032219 |
| Publisher version: | https://doi.org/10.1242/dmm.032219 |
| Language: | English |
| Additional information: | 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: | Neural tube, Vangl2, Biomechanics, F-actin, Mouse, Embryo |
| 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 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10046698 |
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