Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly¹. The axon initial segment (AIS) is a specialized domain that separates a neuron’s morphologically, biochemically and functionally distinct axon and dendrite compartments^2,3. How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism that is likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.

神经元是高度极化的细胞，它们面临的基本挑战是划分大量多样的蛋白质以正常发挥作用¹。轴突初始段 (AIS) 是一个专门的域，它将神经元的形态、生化和功能上不同的轴突和树突隔间^2,3分开。AIS 如何保持这些隔间之间的极性尚不完全清楚。在这里我们发现在秀丽隐杆线虫、小鼠、大鼠和人类神经元，树突和轴突极化的跨膜蛋白被 AIS 中的内吞机制识别，强烈内吞并靶向晚期内体进行降解。强迫受体与 AIS 主要组织者 ankyrinG 相互作用，拮抗 AIS 中的受体内吞作用，导致 AIS 中的受体积累，并导致极性缺陷以及随后的形态和行为缺陷。因此，内吞去除扩散到 AIS 中的极化受体作为一种膜清除机制，可能与已知的 AIS 扩散屏障机制一起工作，以维持质膜上的神经元极性。