在神经元迁移过程中,细胞质动力蛋白yank在微管上产生的力从中心体延伸到引导过程,并沿着在中心体后面延伸的微管移动细胞核。脚手架,比如放射状胶质,引导神经元从脑室向外迁移,但是对于确保soma沿着其适当路径迁移而不是向后移动或偏离路径的内部机制知之甚少。在这里,我们报告了KIFC1的消耗,一种称为HSET的负端定向驱动蛋白,导致神经元迁移到适当的路径,这表明这种分子马达是确保迁移轨迹保真度的原因。对于这些研究,我们在体外使用大鼠游走神经元,在体内使用小鼠大脑发育,以及KIFC1突变形式的RNA干扰和异位表达。我们发现,通过KIFC1将微管交联成非滑动模式对于动力蛋白驱动力实现足够的牵引力以向前推动体细胞是必需的。由KIFC1驱动的微管滑动的不对称回合,从而使体向一个方向或另一个方向倾斜,从而提供中间校正,使神经元保持在其适当的轨迹上。KIFC1驱动的微管滑动通过允许细胞核在移动时定向旋转,进一步帮助神经元保持在其适当的路径上。这与我们发现KIFC1在神经元发育的早期阶段有助于动力间核迁移的方式一致。重要声明解决神经元迁移的机制在医学上很重要,因为许多大脑发育障碍涉及神经元迁移的缺陷,并且因为新生神经元的部署在成年人中对于认知和记忆可能很重要。抑制KIFC1的药物是化疗的候选药物,因此如果允许它们进入大脑,应谨慎使用。
During neuronal migration, forces generated by cytoplasmic dynein yank on microtubules extending from the centrosome into the leading process and move the nucleus along microtubules that extend behind the centrosome. Scaffolds, such as radial glia, guide neuronal migration outward from the ventricles, but little is known about the internal machinery that ensures that the soma migrates along its proper path rather than moving backward or off the path. Here we report that depletion of KIFC1, a minus-end-directed kinesin called HSET in humans, causes neurons to migrate off their appropriate path, suggesting that this molecular motor is what ensures fidelity of the trajectory of migration. For these studies, we used rat migratory neurons in vitro and developing mouse brain in vivo, together with RNA interference and ectopic expression of mutant forms of KIFC1. We found that crosslinking of microtubules into a nonsliding mode by KIFC1 is necessary for dynein-driven forces to achieve sufficient traction to thrust the soma forward. Asymmetric bouts of microtubule sliding driven by KIFC1 thereby enable the soma to tilt in one direction or another, thus providing midcourse corrections that keep the neuron on its appropriate trajectory. KIFC1-driven sliding of microtubules further assists neurons in remaining on their appropriate path by allowing the nucleus to rotate directionally as it moves, which is consistent with how we found that KIFC1 contributes to interkinetic nuclear migration at an earlier stage of neuronal development.SIGNIFICANCE STATEMENT Resolving the mechanisms of neuronal migration is medically important because many developmental disorders of the brain involve flaws in neuronal migration and because deployment of newly born neurons may be important in the adult for cognition and memory. Drugs that inhibit KIFC1 are candidates for chemotherapy and therefore should be used with caution if they are allowed to enter the brain.