Rho-kinase-dependent actin turnover and actomyosin disassembly are necessary for mouse spinal neural tube closure.
Rho-kinase-dependent actin turnover and actomyosin disassembly are necessary for mouse spinal neural tube closure.
复制标题
DOI：
10.1242/jcs.164574
复制
发表时间：
2015-07-15
影响因子：
4
通讯作者：
Copp AJ
中科院分区：
文献类型：
--
作者：
Escuin S;Vernay B;Savery D;Gurniak CB;Witke W;Greene ND;Copp AJ
细胞骨架被广泛认为对神经发育至关重要，然而尽管细胞骨架受到遗传和非遗传破坏，小鼠脊髓神经管仍能关闭。为了研究这种明显的矛盾，我们将细胞骨架抑制剂应用于培养的小鼠胚胎。防止肌动球蛋白交联、f -肌动蛋白组装或肌动蛋白II收缩活动不会破坏脊髓闭合。相反，抑制Rho激酶（ROCK，其有两个同工型ROCK1和ROCK2）或阻断f -肌动蛋白的分解会阻止闭合，导致神经上皮的顶端f -肌动蛋白积累和粘附连接紊乱。没有cofilin -1的胚胎产生了类似的表型，支持了肌动蛋白转换起关键作用的假设。共同暴露于Blebbistatin可以挽救由RhoA抑制引起的神经缺损，而肌球蛋白轻链激酶抑制剂ML-7则没有这种效果。我们得出结论，RhoA， Rho激酶，LIM激酶和cofilin信号的调节是通过精确控制神经上皮肌动蛋白的转换和肌动球蛋白的分解来关闭脊髓神经管的必要条件。相反，肌动球蛋白组装和肌凝蛋白atp酶活性不受关闭的限制。摘要：肌动球蛋白组装和肌球蛋白atp酶活性对小鼠脊髓神经发育并不是必需的。然而，ROCK-LIMK-cofilin通路是必需的，它控制着肌动蛋白的周转和肌动球蛋白的分解。
The cytoskeleton is widely considered essential for neurulation, yet the mouse spinal neural tube can close despite genetic and non-genetic disruption of the cytoskeleton. To investigate this apparent contradiction, we applied cytoskeletal inhibitors to mouse embryos in culture. Preventing actomyosin cross-linking, F-actin assembly or myosin II contractile activity did not disrupt spinal closure. In contrast, inhibiting Rho kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) or blocking F-actin disassembly prevented closure, with apical F-actin accumulation and adherens junction disturbance in the neuroepithelium. Cofilin-1-null embryos yielded a similar phenotype, supporting the hypothesis that there is a key role for actin turnover. Co-exposure to Blebbistatin rescued the neurulation defects caused by RhoA inhibition, whereas an inhibitor of myosin light chain kinase, ML-7, had no such effect. We conclude that regulation of RhoA, Rho kinase, LIM kinase and cofilin signalling is necessary for spinal neural tube closure through precise control of neuroepithelial actin turnover and actomyosin disassembly. In contrast, actomyosin assembly and myosin ATPase activity are not limiting for closure. Summary: Actomyosin assembly and myosin ATPase activity are not essential for mouse spinal neurulation. However, the ROCK–LIMK–cofilin pathway, which controls actin turnover and actomyosin disassembly, is necessary.