Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.
Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, United States.
Elife. 2021 Mar 24;10:e63532. doi: 10.7554/eLife.63532.
Glia in the central nervous system engulf neuron fragments to remodel synapses and recycle photoreceptor outer segments. Whether glia passively clear shed neuronal debris or actively prune neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here, we report our discovery of glia-directed neuron pruning in Adult AMsh glia engulf sensory endings of the AFD thermosensory neuron by repurposing components of the conserved apoptotic corpse phagocytosis machinery. The phosphatidylserine (PS) flippase TAT-1/ATP8A functions with glial PS-receptor PSR-1/PSR and PAT-2/α-integrin to initiate engulfment. This activates glial CED-10/Rac1 GTPase through the ternary GEF complex of CED-2/CrkII, CED-5/DOCK180, CED-12/ELMO. Execution of phagocytosis uses the actin-remodeler WSP-1/nWASp. This process dynamically tracks AFD activity and is regulated by temperature, the AFD sensory input. Importantly, glial CED-10 levels regulate engulfment rates downstream of neuron activity, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underlying glia-dependent engulfment in a peripheral sense-organ and demonstrate that glia actively engulf neuron fragments, with profound consequences on neuron shape and animal sensory behavior.
中枢神经系统中的神经胶质细胞吞噬神经元碎片以重塑突触并回收光感受器外节。目前尚不清楚神经胶质细胞是被动清除脱落的神经元碎片，还是主动修剪神经元碎片。修剪单个神经元末梢如何影响动物行为也不清楚。在这里，我们报告了我们在成年 AMsh 神经胶质细胞中发现的神经胶质细胞导向的神经元修剪，成年 AMsh 神经胶质细胞通过重新利用保守的凋亡细胞吞噬机制的组件吞噬 AFD 热敏神经元的感觉末梢。磷脂酰丝氨酸（PS）翻转酶 TAT-1/ATP8A 与神经胶质 PS 受体 PSR-1/PSR 和 PAT-2/α-整合素一起作用，启动吞噬作用。这通过 CED-2/CrkII、CED-5/DOCK180、CED-12/ELMO 的三元 GEF 复合物激活神经胶质 CED-10/Rac1 GTPase。吞噬作用的执行使用肌动蛋白重排蛋白 WSP-1/nWASp。这个过程动态跟踪 AFD 的活动，并受温度、AFD 感觉输入的调节。重要的是，神经胶质细胞 CED-10 水平调节神经元活动下游的吞噬作用速率，吞噬作用缺陷突变体表现出 AFD 末梢形状和热敏感觉行为的改变。我们的发现揭示了一个分子途径，为外周感觉器官中依赖神经胶质细胞的吞噬作用提供了基础，并证明了神经胶质细胞主动吞噬神经元碎片，这对神经元形状和动物感觉行为有深远的影响。
