Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos. (February 2018)

• Record Type: Journal Article
• Authors: Hughes, Amy; Greene, Nicholas D.E.; Copp, Andrew J.; Galea, Gabriel L.
• Is Part Of: Mechanisms of development. Volume 149(2017)
• Page Start: 20
• Page End: 26
• Publication Date: 2018-02
• Subjects: Neural tube -- Valproic acid -- Mouse -- Closure 5 -- Biomechanics; Developmental biology -- Periodicals; Molecular biology -- Periodicals; Developmental Biology -- Periodicals; Molecular Biology -- Periodicals; Biologie du développement -- Périodiques; Biologie moléculaire -- Périodiques; Developmental biology; Molecular biology; Periodicals; Electronic journals; 571.8
• DOI: 10.1016/j.mod.2017.12.001
• Languages: English
• ISSNs: 0925-4773

Abstract

Abstract: Failure of neural tube closure in the early embryo causes neural tube defects including spina bifida. Spina bifida lesions predominate in the distal spine, particularly after exposure to the anticonvulsant valproic acid (VPA). How VPA specifically disturbs late stages of neural tube closure is unclear, as neurulation is usually viewed as a uniform 'zippering' process along the spine. We recently identified a novel closure site ("Closure 5") which forms at the caudal extremity of the mouse posterior neuropore (PNP) when completion of closure is imminent. Here we investigated whether distal spina bifida in VPA-exposed embryos involves disruption of Closure 5. Exposure of E8.5 mouse embryos to VPA in whole embryo culture had marked embryotoxic effects, whereas toxic effects were less pronounced in more developmentally advanced (E9) embryos. Only 33% of embryos exposed to VPA from E9 to E10.5 achieved PNP closure (control = 90%). Short-term (8 h) VPA treatment diminished supra-cellular F-actin cables which normally run along the lateral neural folds, and prevented caudal PNP narrowing normally characteristic of Closure 5 formation. Laser ablation of Closure 5 caused rapid neuropore widening. Equivalent ablations of the caudal PNP in VPA treated embryos resulted in significantly less widening, suggesting VPA prevents formation of Closure 5 as a biomechanically active structure. Thus, VPA exposure prevents morphological and biomechanical conversion of the caudal extreme of the PNP during late spinal closure. Closure 5 facilitates neural fold apposition when completion of closure is imminent, such that its disruption in VPA-exposed embryos may lead to distal spina bifida. Highlights: Exposure of mouse embryos to valproate diminishes posterior neuropore closure. Valproate treatment prevents caudal neuropore narrowing at late neurulation stages. Valproate diminished F-actin cables normally present along the neural folds. Laser ablation of the neuropore's caudal extreme normally causes rapid widening. Valproate abolishes the caudal neuropore's biomechanical contributions to closure.