The Death Receptor CD95 Activates Adult Neural Stem Cells for Working Memory Formation and Brain Repair
The Death Receptor CD95 Activates Adult Neural Stem Cells for Working Memory Formation and Brain Repair
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DOI：
10.1016/j.stem.2009.05.004
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发表时间：
2009-08-07
期刊：
影响因子：
23.9
通讯作者：
Martin-Villalba, Ana
中科院分区：
文献类型：
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作者：
Corsini, Nina S.;Sancho-Martinez, Ignacio;Martin-Villalba, Ana
成体神经发生持续存在于脑室下区和齿状回，并可在中枢神经系统损伤时诱导。然而，新生神经元对神经元网络的最终贡献是有限的。在这里，我们表明，在神经干细胞中，刺激“死亡受体”CD95不会引发细胞凋亡，但会意外地导致干细胞存活和神经元规格的增加。这些作用是通过激活Src/PI3K/AKT/mTOR信号通路，最终导致蛋白质翻译的全球增加而实现的。CD95在缺血的CA1区、幼稚的齿状回以及在成人室下区强制表达CD95L后，进一步证实了CD95诱导神经发生的作用。缺乏海马区CD95导致神经发生和工作记忆缺陷的减少。全脑缺血后，CD95介导的脑修复挽救了行为障碍。因此，我们认为CD95/CD95L系统是正在进行的和损伤诱导的神经发生的指导性信号。
Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury. However, the final contribution of newborn neurons to neuronal networks is limited. Here we show that in neural stem cells, stimulation of the "death receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repair rescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis.