Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human.
Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human.
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DOI：
10.1093/brain/awab317
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发表时间：
2022-04-18
期刊：
影响因子：
14.5
通讯作者：
Zhou, Libing
中科院分区：
文献类型：
--
作者：
Wen, Quan;Weng, Huandi;Liu, Tao;Yu, Lingtai;Zhao, Tainyun;Qin, Jingwen;Li, Si;Wu, Qingfeng;Fadel, Tissir;Qu, Yibo;Zhou, Libing
了解轴突再生的新调节剂是神经修复的核心。我们之前的工作证明了非典型钙粘蛋白Celsr2在神经发育过程中的关键作用，包括纤毛组织、神经元迁移和轴突导航。在这里，我们讨论了它在轴突再生中的作用。我们发现Celsr2在小鼠和人的脊髓运动神经元中都是高表达的。敲除Celsr2促进小鼠培养的脊髓外植体轴突再生和束状化。同样，培养的Celsr2突变体运动神经元的神经突更长，生长锥更大，末端结合蛋白3的表达增加，钾诱导的钙内流增加。脊髓运动神经元中有条件敲除Celsr2的小鼠没有表现出任何行为缺陷；然而，臂丛损伤后，轴突再生和前肢功能运动恢复明显改善。同样，在培养的人脊髓运动外植体和运动神经元中，使用shRNA干扰敲低CELSR2可增加轴突的束状突起和生长。在根撕脱后的小鼠成年脊髓、小鼠胚胎脊髓和培养的人运动神经元中，Celsr2下调伴随着gtp结合的Rac1和Cdc42以及JNK和c-Jun水平的升高。综上所述，Celsr2负调控运动轴突再生，是改善神经修复的潜在靶点。请参阅Petrova和Hakim （https://doi.org/10.1093/brain/awac021）对本文的科学评论。Wen等人发现Celsr2是轴突再生的负调节因子。Celsr2失活可促进小鼠和人脊髓运动神经元轴突再生，以及小鼠鳃裂丛损伤后前肢功能恢复。这些过程与Rac1/Cdc42-JNK/c-Jun信号的上调相关。
Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair. See Petrova and Hakim (https://doi.org/10.1093/brain/awac021) for a scientific commentary on this article. Wen et al. identify Celsr2 as a negative regulator of axon regeneration. Celsr2 inactivation promotes axon regeneration in both mouse and human spinal motor neurons, and functional forelimb recovery after branchial plexus injury in mice. These processes correlate with upregulation of Rac1/Cdc42-JNK/c-Jun signalling.
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