Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Neurology, Yale University, New Haven, CT 06536, USA.
Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536, USA; Department of Genetics, Yale University, New Haven, CT 06536, USA.
Cell Rep. 2018 Apr 10;23(2):415-428. doi: 10.1016/j.celrep.2018.03.058.
Axonal regrowth is crucial for recovery from CNS injury but is severely restricted in adult mammals. We used a genome-wide loss-of-function screen for factors limiting axonal regeneration from cerebral cortical neurons in vitro. Knockdown of 16,007 individual genes identified 580 significant phenotypes. These molecules share no significant overlap with those suggested by previous expression profiles. There is enrichment for genes in pathways related to transport, receptor binding, and cytokine signaling, including Socs4 and Ship2. Among transport-regulating proteins, Rab GTPases are prominent. In vivo assessment with C. elegans validates a cell-autonomous restriction of regeneration by Rab27. Mice lacking Rab27b show enhanced retinal ganglion cell axon regeneration after optic nerve crush and greater motor function and raphespinal sprouting after spinal cord trauma. Thus, a comprehensive functional screen reveals multiple pathways restricting axonal regeneration and neurological recovery after injury.
轴突再生对于中枢神经系统损伤的恢复至关重要，但在成年哺乳动物中受到严重限制。我们使用全基因组功能丧失筛选，以确定体外大脑皮质神经元轴突再生的限制因素。敲低 16007 个基因，鉴定出 580 个显著表型。这些分子与之前的表达谱提示的分子没有明显重叠。在与运输、受体结合和细胞因子信号转导相关的途径中，存在丰富的基因，包括 Socs4 和 Ship2。在调节蛋白中，Rab GTPases 很突出。利用秀丽隐杆线虫进行体内评估，验证了 Rab27 对再生的自主限制。缺乏 Rab27b 的小鼠在视神经挤压后表现出视网膜神经节细胞轴突再生增强，以及脊髓损伤后运动功能和中缝脊髓投射增强。因此，全面的功能筛选揭示了多种限制损伤后轴突再生和神经恢复的途径。
