Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos.
Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos.
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DOI：
10.1016/j.mod.2017.12.001
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发表时间：
2018-03
影响因子：
2.6
通讯作者：
Galea GL
中科院分区：
文献类型：
--
作者：
Hughes A;Greene NDE;Copp AJ;Galea GL
胚胎早期神经管闭合失败导致神经管缺陷，包括脊柱裂。脊柱裂病变主要发生在脊柱远端，特别是暴露于抗惊厥药丙戊酸（VPA）后。VPA如何特异性地干扰神经管闭合的后期阶段尚不清楚，因为神经发育通常被视为沿脊柱均匀的“拉链”过程。我们最近发现了一个新的关闭位点（“关闭5”），当关闭即将完成时，它在小鼠后神经孔（PNP）的尾端形成。在这里，我们研究了暴露于vpa的胚胎的远端脊柱裂是否涉及闭合5的破坏。E8.5小鼠胚胎在全胚胎培养中暴露于VPA有明显的胚胎毒性作用，而在发育较晚（E9）的胚胎中，毒性作用不太明显。从E9到E10.5暴露于VPA的胚胎中，只有33%的胚胎实现了PNP闭合（对照组= 90%）。短期（8小时）VPA治疗减少了通常沿外侧神经褶皱运行的细胞上f -肌动蛋白电缆，并阻止了尾端PNP狭窄，这通常是闭包5形成的特征。激光消融闭合5导致神经孔快速扩张。在VPA处理的胚胎中，尾端PNP的等效消融导致显着减少拓宽，这表明VPA阻止了Closure 5的形成，这是一种生物力学活性结构。因此，VPA暴露可在脊柱闭合后期阻止PNP尾侧极端的形态和生物力学转换。当关闭即将完成时，关闭5促进神经褶皱的靠近，因此暴露于vpa的胚胎中关闭5的破坏可能导致远端脊柱裂。小鼠胚胎暴露于丙戊酸减少后神经孔关闭。丙戊酸治疗可防止神经发育后期尾侧神经孔狭窄。丙戊酸降低了沿神经褶皱正常存在的肌动蛋白索。激光消融神经孔尾部末端通常会导致神经孔迅速扩大。丙戊酸消除了尾侧神经孔对闭合的生物力学贡献。
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. 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.
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DOI：
10.1073/pnas.1700934114
发表时间：
2017-06-27
影响因子：
11.1
作者：
Galea, Gabriel L.;Cho, Young-June;Copp, Andrew J.
通讯作者：
Copp, Andrew J.
影响因子：
3.8
作者：
Lampen, A;Siehler, S;Nau, H
通讯作者：
Nau, H
影响因子：
4.8
作者：
Samant, Sadhana A.;Pillai, Vinodkumar B.;Gupta, Mahesh P.
通讯作者：
Gupta, Mahesh P.
DOI：
10.1002/tera.1420430206
发表时间：
1991-02-01
期刊：
TERATOLOGY
影响因子：
--
作者：
SEEGMILLER, RE;HARRIS, C;JUCHAU, MR
通讯作者：
JUCHAU, MR
影响因子：
3.7
作者：
Corena-McLeod M;Walss-Bass C;Oliveros A;Gordillo Villegas A;Ceballos C;Charlesworth CM;Madden B;Linser PJ;Van Ekeris L;Smith K;Richelson E
通讯作者：
Richelson E