Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou 510632, P. R. China.
Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, P. R. China.
Brain. 2022 Apr 18;145(2):670-683. doi: 10.1093/brain/awab317.
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.
了解轴突再生的新调节因子是神经修复的核心。我们之前的工作表明，非典型钙黏蛋白 Celsr2 在神经发育过程中起着关键作用，包括纤毛组织、神经元迁移和轴突导航。在这里，我们研究了它在轴突再生中的作用。我们发现 Celsr2 在小鼠和人类脊髓运动神经元中均高度表达。Celsr2 敲除促进小鼠培养脊髓外植体中的轴突再生和聚集。同样，培养的 Celsr2 突变型运动神经元延伸出更长的轴突和更大的生长锥，末端结合蛋白 3 的表达增加，钾诱导的钙内流增加。在脊髓运动神经元中条件性敲除 Celsr2 的小鼠没有表现出任何行为缺陷；然而，在鳃弓神经损伤后，轴突再生和功能性前肢运动恢复显著改善。同样，在培养的人类脊髓运动外植体和运动神经元中使用 shRNA 干扰敲低 CELSR2 可增加轴突聚集和生长。在神经根撕脱后的成年小鼠脊髓、小鼠胚胎脊髓和培养的人运动神经元中，Celsr2 的下调伴随着 GTP 结合 Rac1 和 Cdc42 以及 JNK 和 c-Jun 的水平增加。总之，Celsr2 负调节运动轴突再生，是改善神经修复的潜在靶点。
