JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death.
JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death.
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DOI：
10.1016/j.nbd.2012.02.003
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发表时间：
2012-05
影响因子：
6.1
通讯作者：
Libby, Richard T.
中科院分区：
文献类型：
--
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
关键词：
青光眼是一种以视网膜神经节细胞(RGC)的凋亡性死亡为特征的神经退行性疾病。青光眼患者对视网膜节细胞的主要侮辱被认为发生在它们的轴突上，因为它们离开了视神经头部的眼睛。然而，在轴突损伤后触发RGC死亡中发挥核心作用的病理信号通路仍不清楚。轴突损伤后发生的第一个变化很可能是将损伤信号从轴突传递到细胞体的信号传递事件。在这里，我们关注c-jun氨基末端激酶(JNK1-3)家族，这一信号通路与轴突损伤信号转导和神经退行性细胞凋亡有关，并可能在轴突损伤诱导的RGC死亡中发挥中心节点的作用。我们发现JNK信号在轴突损伤后立即在损伤部位的RGC轴突中被激活。在其早期激活后，在轴突损伤的视网膜节细胞中观察到持续的JNK信号以Jun磷酸化和上调的形式存在。利用缺乏JNK亚型的小鼠，我们证明了JNK2和JNK3是损伤轴突中被激活的亚型。JNK2和JNK3的联合缺失对轴突损伤诱导的RGC死亡提供了强大的长期保护，并阻止了RGC标记物BRN3B的下调和Jun的磷酸化。最后，利用Jun缺乏的小鼠，我们证明了Jun依赖的通路在轴突损伤诱导的RGC死亡中是重要的。综上所述，这些数据表明，JNK信号是轴突损伤后触发RGC死亡的主要早期途径，并可能直接将轴突损伤与控制RGC死亡的转录活动联系起来。
Glaucoma is a neurodegenerative disease characterized by the apoptotic death of retinal ganglion cells (RGCs). The primary insult to RGCs in glaucoma is thought to occur to their axons as they exit the eye in the optic nerve head. However, pathological signaling pathways that exert central roles in triggering RGC death following axonal injury remain unidentified. It is likely that the first changes to occur following axonal injury are signal relay events that transduce the injury signal from the axon to the cell body. Here we focus on the c-Jun N-terminal kinase (JNK1-3) family, a signaling pathway implicated in axonal injury signaling and neurodegenerative apoptosis, and likely to function as a central node in axonal injury-induced RGC death. We show that JNK signaling is activated immediately after axonal injury in RGC axons at the site of injury. Following its early activation, sustained JNK signaling is observed in axonally-injured RGCs in the form of JUN phosphorylation and upregulation. Using mice lacking specific Jnk isoforms, we show that Jnk2 and Jnk3 are the isoforms activated in injured axons. Combined deficiency of Jnk2 and Jnk3 provides robust long-term protection against axonal injury-induced RGC death and prevents downregulation of the RGC marker, BRN3B, and phosphorylation of JUN. Finally, using Jun deficient mice, we show that JUN-dependent pathways are important for axonal injury-induced RGC death. Together these data demonstrate that JNK signaling is the major early pathway triggering RGC death after axonal injury and may directly link axon injury to transcriptional activity that controls RGC death.
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