Biomechanical coupling facilitates spinal neural tube closure in mouse embryos
Biomechanical coupling facilitates spinal neural tube closure in mouse embryos
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DOI：
10.1073/pnas.1700934114
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发表时间：
2017-06-27
影响因子：
11.1
通讯作者：
Copp, Andrew J.
中科院分区：
文献类型：
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作者：
Galea, Gabriel L.;Cho, Young-June;Copp, Andrew J.
哺乳动物胚胎脊髓区域的神经管（NT）形成涉及一波“拉链”，该“拉链”沿着伸长的脊髓轴向下传递，将背中线的神经褶皱尖端联合起来。这种闭合过程的失败导致开放性脊柱裂，这是人类严重神经功能障碍的常见原因。在这里，我们结合了组织水平的应变映射工作流程与激光消融活成像小鼠胚胎，以研究哺乳动物脊柱闭合的生物力学。在胚胎背中线的拉链点的消融导致了提升神经褶皱的深远的，快速的分离。应变分析显示，消融后拉链点周围的组织扩张，但主要组织收缩在尾侧和腹侧神经板区。该区域通过细胞外F-肌动蛋白网络与拉链点生物力学耦合，该网络包括沿着神经褶皱尖端延伸的肌动蛋白索。F-肌动蛋白的药理学抑制或电缆的激光消融导致神经褶皱分离。在最先进的体节阶段，当完成脊髓即将关闭，电缆形成一个连续的环周围的神经孔，同时，一个新的尾部到喙拉链点出现。激光消融这个新的闭合起始点导致神经褶皱分离，证明了其生物力学活性。脊柱裂前Zic 2（Ku）突变胚胎的脊柱闭合失败与组织生物力学改变有关，如消融后神经孔扩大所示。因此，这项研究确定了生物力学耦合的整个区域的活跃的脊髓神经形成在小鼠胚胎成功NT关闭的先决条件。
Neural tube (NT) formation in the spinal region of the mammalian embryo involves a wave of "zippering" that passes down the elongating spinal axis, uniting the neural fold tips in the dorsal midline. Failure of this closure process leads to open spina bifida, a common cause of severe neurologic disability in humans. Here, we combined a tissue-level strain-mapping workflow with laser ablation of live-imaged mouse embryos to investigate the biomechanics of mammalian spinal closure. Ablation of the zippering point at the embryonic dorsal midline causes far-reaching, rapid separation of the elevating neural folds. Strain analysis revealed tissue expansion around the zippering point after ablation, but predominant tissue constriction in the caudal and ventral neural plate zone. This zone is biomechanically coupled to the zippering point by a supracellular F-actin network, which includes an actin cable running along the neural fold tips. Pharmacologic inhibition of F-actin or laser ablation of the cable causes neural fold separation. At the most advanced somite stages, when completion of spinal closure is imminent, the cable forms a continuous ring around the neuropore, and simultaneously, a new caudal-to-rostral zippering point arises. Laser ablation of this new closure initiation point causes neural fold separation, demonstrating its biomechanical activity. Failure of spinal closure in pre-spina bifida Zic2(Ku) mutant embryos is associated with altered tissue biomechanics, as indicated by greater neuropore widening after ablation. Thus, this study identifies biomechanical coupling of the entire region of active spinal neurulation in the mouse embryo as a prerequisite for successful NT closure.