Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury.

Preethi Somasundaram, Madeline M Farley, Melissa A Rudy, Katya Sigal, Andoni I Asencor, David G Stefanoff, Malay Shah, Puneetha Goli, Jenny Heo, Shufang Wang, Nicholas M Tran, Trent A Watkins
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Abstract

Stress signaling is important for determining the fates of neurons following axonal insults. Previously we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here we show that PERK acts primarily through Activating Transcription Factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.

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视神经损伤后 Atf4 对轴突再生和神经退行性转录程序的协调刺激
此前我们曾发现,轴突损伤引发的神经退行性变部分取决于应激反应激酶Perk(Larhammar等人,2017年)。在这里,我们发现 Perk 主要通过活化转录因子-4(Atf4)发挥作用,在视神经损伤后不仅刺激促凋亡反应,还刺激促再生反应。利用条件性基因敲除小鼠,我们发现了广泛的 Perk/Atf4 依赖性转录反应,其中包括典型的 Atf4 靶基因和 C/ebp 同源蛋白(Chop)的适度贡献。与 c-Jun 依赖性转录的重叠表明,与再生和凋亡反应相关的平行应激途径也在发挥作用。因此,神经元敲除 Atf4 可重现 Perk 缺乏所提供的神经保护,而 Perk 或 Atf4 的敲除会损害肿瘤抑制因子 Pten 所实现的视轴突再生。这些发现与所报道的CRISPR靶向Atf4或Chop的转录和功能后果形成了鲜明对比,并揭示了Perk/Atf4在协调神经退行性病变和中枢神经系统轴突损伤再生反应中不可或缺的作用。
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