Neurons are highly polarized cells that are composed of a single axon and multiple dendrites. Axon–dendrite polarity is essential for proper tissue formation and brain functions. Intracellular protein transport plays an important role in the establishment of neuronal polarity. However, the regulatory mechanism of polarized transport remains unclear. Here, we show that Rab6, a small GTPase that acts on the regulation of intracellular vesicular trafficking, plays key roles in neuronal polarization and brain development. Central nervous system-specific Rab6a/b double knock-out (Rab6 DKO) mice of both sexes exhibit severe dysplasia of the neocortex and the cerebellum. In the Rab6 DKO neocortex, impaired axonal extension of neurons results in hypoplasia of the intermediate zone. In vitro, deletion of Rab6a and Rab6b in cultured neurons from both sexes causes the abnormal accumulation of synaptic vesicle precursors (SVPs) adjacent to the Golgi apparatus, which leads to defects in axonal extension and the loss of axon–dendrite polarity. Moreover, Rab6 DKO causes significant expansion of lysosomes in the soma in neurons. Overall, our results reveal that Rab6-mediated polarized transport of SVPs is crucial for neuronal polarization and subsequent brain formation.

神经元是高度极化的细胞，由单个轴突和多个树突组成。轴突-树突极性对于正常的组织形成和大脑功能至关重要。细胞内蛋白质转运在神经元极性的建立中起着重要作用。然而，极化传输的调控机制仍不清楚。在这里，我们证明 Rab6 是一种小型 GTP 酶，作用于细胞内囊泡运输的调节，在神经元极化和大脑发育中发挥关键作用。中枢神经系统特异性 Rab6a/b 双敲除 (Rab6 DKO) 雌雄小鼠均表现出严重的新皮质和小脑发育不良。在 Rab6 DKO 新皮质中，神经元轴突延伸受损导致中间区发育不全。在体外，培养的两性神经元中 Rab6a 和 Rab6b 的缺失会导致高尔基体附近突触小泡前体 (SVP) 的异常积累，从而导致轴突延伸缺陷和轴突树突极性丧失。此外，Rab6 DKO 会导致神经元胞体中溶酶体的显着扩张。总的来说，我们的结果表明 Rab6 介导的 SVP 极化运输对于神经元极化和随后的大脑形成至关重要。