For the proper organization of the six-layered mammalian neocortex it is required that neurons migrate radially from their place of birth towards their designated destination. The molecular machinery underlying this neuronal migration is still poorly understood. The dynein-adaptor protein BICD2 is associated with a spectrum of human neurological diseases, including malformations of cortical development. Previous studies have shown that knockdown of BICD2 interferes with interkinetic nuclear migration in radial glial progenitor cells, and that Bicd2-deficient mice display an altered laminar organization of the cerebellum and the neocortex. However, the precise in vivo role of BICD2 in neocortical development remains unclear. By comparing cell-type specific conditional Bicd2 knock-out mice, we found that radial migration in the cortex predominantly depends on BICD2 function in post-mitotic neurons. Neuron-specific Bicd2 cKO mice showed severely impaired radial migration of late-born upper-layer neurons. BICD2 depletion in cortical neurons interfered with proper Golgi organization, and neuronal maturation and survival of cortical plate neurons. Single-neuron labeling revealed a specific role of BICD2 in bipolar locomotion. Rescue experiments with wildtype and disease-related mutant BICD2 constructs revealed that a point-mutation in the RAB6/RANBP2-binding-domain, associated with cortical malformation in patients, fails to restore proper cortical neuron migration. Together, these findings demonstrate a novel, cell-intrinsic role of BICD2 in cortical neuron migration in vivo and provide new insights into BICD2-dependent dynein-mediated functions during cortical development.

中文翻译：

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动力蛋白激活适配器BICD2控制体内上层皮层神经元的径向迁移。

为了正确组织六层的哺乳动物新皮层，需要神经元从其出生地向其指定目的地放射状迁移。这种神经元迁移的分子机制仍然知之甚少。动力蛋白适应蛋白BICD2与一系列人类神经系统疾病有关，包括皮质发育畸形。先前的研究表明，敲除BICD2会干扰放射状神经胶质祖细胞中的运动间核迁移，并且Bicd2缺陷型小鼠的小脑和新皮层的层状组织会发生变化。但是，尚不清楚BICD2在新皮层发育中的确切体内作用。通过比较细胞类型的特定条件性Bicd2敲除小鼠，我们发现皮质中的径向迁移主要取决于有丝分裂后神经元中的BICD2功能。神经元特异性Bicd2 cKO小鼠显示晚期出生的上层神经元的径向迁移受到严重损害。皮质神经元中的BICD2耗竭会干扰正常的高尔基体组织，以及皮质板神经元的神经元成熟和存活。单神经元标记揭示了BICD2在双极运动中的特定作用。用野生型和与疾病相关的突变体BICD2构建体进行的抢救实验表明，RAB6 / RANBP2结合域中的点突变与患者的皮质畸形相关，无法恢复正常的皮质神经元迁移。这些发现共同证明了一部小说，