Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY, USA.
Exp Eye Res. 2013 Jul;112:106-17. doi: 10.1016/j.exer.2013.04.021. Epub 2013 May 3.
The AP1 family transcription factor JUN is an important molecule in the neuronal response to injury. In retinal ganglion cells (RGCs), JUN is upregulated soon after axonal injury and disrupting JUN activity delays RGC death. JUN is known to participate in the control of many different injury response pathways in neurons, including pathways controlling cell death and axonal regeneration. The role of JUN in regulating genes involved in cell death, ER stress, and regeneration was tested to determine the overall importance of JUN in regulating RGC response to axonal injury. Genes from each of these pathways were transcriptionally controlled following axonal injury and Jun deficiency altered the expression of many of these genes. The differentially expressed genes included, Atf3, Ddit3, Ecel1, Gadd45α, Gal, Hrk, Pten, Socs3, and Sprr1a. Two of these genes, Hrk and Atf3, were tested for importance in RGC death using null alleles of each gene. Disruption of the prodeath Bcl2 family member Hrk did not affect the rate or amount of RGC death after axonal trauma. Deficiency in the ATF/CREB family transcription factor Atf3 did lessen the amount of RGC death after injury, though it did not provide long term protection to RGCs. Since JUN's dimerization partner determines its transcriptional targets, the expression of several candidate AP1 family members were examined. Multiple AP1 family members were induced by axonal injury and had a different expression profile in Jun deficient retinas compared to wildtype retinas (Fosl1, Fosl2 and Jund). Overall, JUN appears to play a multifaceted role in regulating RGC response to axonal injury.
AP1 家族转录因子 JUN 是神经元对损伤反应的重要分子。在视网膜神经节细胞（RGCs）中，JUN 在轴突损伤后很快上调，破坏 JUN 活性会延迟 RGC 死亡。众所周知，JUN 参与神经元中许多不同的损伤反应途径的控制，包括控制细胞死亡和轴突再生的途径。测试了 JUN 在调节参与细胞死亡、内质网应激和再生的基因中的作用，以确定 JUN 在调节 RGC 对轴突损伤反应中的总体重要性。这些途径中的基因在轴突损伤后转录受到控制，而 Jun 缺陷改变了许多这些基因的表达。差异表达的基因包括 Atf3、Ddit3、Ecel1、Gadd45α、Gal、Hrk、Pten、Soc3 和 Sprr1a。其中两个基因，Hrk 和 Atf3，使用每个基因的 null 等位基因测试了它们在 RGC 死亡中的重要性。破坏促凋亡 Bcl2 家族成员 Hrk 不会影响轴突创伤后 RGC 死亡的速度或数量。ATF/CREB 家族转录因子 Atf3 的缺失确实减轻了损伤后 RGC 死亡的数量，但并没有为 RGC 提供长期保护。由于 JUN 的二聚化伙伴决定其转录靶标，因此检查了几种候选 AP1 家族成员的表达。几种 AP1 家族成员被轴突损伤诱导，并且在 Jun 缺陷视网膜中与野生型视网膜相比具有不同的表达谱（Fosl1、Fosl2 和 Jund）。总体而言，JUN 似乎在调节 RGC 对轴突损伤的反应中发挥多方面的作用。
