Mechanical signaling through membrane tension induces somal translocation during neuronal migration

Neurons migrate in a saltatory manner by repeating two distinct steps: extension of the leading process and translocation of the cell body. The former step is critical for determining the migratory route in response to extracellular guidance cues. In the latter step, neurons must generate robust forces that translocate the bulky soma against mechanical barriers of the surrounding three-dimensional environment. However, the link between the leading process extension and subsequent somal translocation remains unknown. By using the membrane tension sensor Flipper-TR and scanning ion conductance microscopy, we show that leading process extension increases plasma membrane tension. The tension elevation activated the mechanosensitive ion channel Tmem63b and triggered Ca2+ influx, leading to actomyosin activation at the rear of the cell. Blockade of this signaling pathway disturbed somal translocation, thereby inhibiting neuronal migration in three-dimensional environments. These data suggest that mechanical signaling through plasma membrane tension and mechano-channels links the leading process extension to somal translocation, allowing rapid and saltatory neuronal migration.

神经元以跳跃式迁移模式行进，其过程需循环执行两个截然不同的步骤：前沿突起（leading process）延伸与细胞体转位。前者在响应细胞外引导信号以确定迁移路径的过程中发挥关键作用。后者阶段中，神经元必须产生足够强劲的力，以克服周围三维环境中的机械屏障，完成体积庞大的胞体（soma）转位。然而，前沿突起延伸与后续胞体转位之间的关联机制仍未明确。本研究借助膜张力传感器Flipper-TR与扫描离子电导显微镜（scanning ion conductance microscopy），证实前沿突起延伸会提升质膜（plasma membrane）张力。质膜张力升高会激活机械敏感性离子通道Tmem63b，并触发钙离子（Ca²+）内流，进而激活细胞后部的肌动蛋白-肌球蛋白复合体（actomyosin）。阻断该信号通路会干扰胞体转位过程，进而抑制三维环境中的神经元迁移。上述数据表明，经由质膜张力与机械敏感通道的机械信号传导，可将前沿突起延伸与胞体转位关联起来，从而实现快速且跳跃式的神经元迁移。