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Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos

Lookup NU author(s): Professor Deborah HendersonORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018. Published by The Company of Biologists Ltd 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.

Publication metadata

Author(s): Galea GL, Nychyk O, Mole MA, Moulding D, Savery D, Nikolopoulou E, Henderson DJ, Greene NDE, Copp AJ

Publication type: Article

Publication status: Published

Journal: DMM Disease Models and Mechanisms

Year: 2018

Volume: 11

Issue: 3

Online publication date: 21/03/2018

Acceptance date: 28/02/2018

Date deposited: 30/05/2018

ISSN (print): 1754-8403

ISSN (electronic): 1754-8411

Publisher: Company of Biologists Ltd

URL: https://doi.org/10.1242/dmm.032219

DOI: 10.1242/dmm.032219

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