Microglial trogocytosis and the complement system regulate axonal pruning in vivo.
Microglial trogocytosis and the complement system regulate axonal pruning in vivo.
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DOI：
10.7554/elife.62167
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发表时间：
2021-03-16
期刊：
影响因子：
7.7
通讯作者：
Ruthazer ES
中科院分区：
文献类型：
--
作者：
Lim TK;Ruthazer ES
小胶质细胞对轴突的部分吞噬作用已在离体制备中得到证实，但尚未在体内直接观察到。调节轴突小胶质细胞的细胞形成及其在神经回路发育中的功能的机制仍然知之甚少。本研究直接观察了小胶质细胞在发育中的非洲爪蟾视网膜回路上对轴突细胞的吞噬作用。我们发现，小胶质细胞调节视网膜神经节细胞轴突的修剪，对黑暗和明亮隐现刺激的适当行为反应很重要。利用生物信息学，我们鉴定了补体激活3的两栖动物调节因子，人类CD46的同源物，作为神经元表达的突触相关补体抑制分子，抑制细胞增生和轴突修剪。利用一种膜结合补体C3融合蛋白，我们证明了补体活性的增强促进了轴突修剪。我们的研究结果支持小胶质细胞通过胞浆作用重塑轴突的模型，神经元可以通过表达补体抑制蛋白来控制这一过程。
Partial phagocytosis—called trogocytosis—of axons by microglia has been documented in ex vivo preparations but has not been directly observed in vivo. The mechanisms that modulate microglial trogocytosis of axons and its function in neural circuit development remain poorly understood. Here, we directly observe axon trogocytosis by microglia in vivo in the developing Xenopus laevis retinotectal circuit. We show that microglia regulate pruning of retinal ganglion cell axons and are important for proper behavioral response to dark and bright looming stimuli. Using bioinformatics, we identify amphibian regulator of complement activation 3, a homolog of human CD46, as a neuronally expressed synapse-associated complement inhibitory molecule that inhibits trogocytosis and axonal pruning. Using a membrane-bound complement C3 fusion protein, we demonstrate that enhancing complement activity enhances axonal pruning. Our results support the model that microglia remodel axons via trogocytosis and that neurons can control this process through expression of complement inhibitory proteins.