University of Leicester and Leicestershire Partnership NHS Trust, Leicester, United Kingdom.
Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Institute of Health, Klinik und Hochschulambulanz für Neurologie und Centrum für Schlaganfallforschung Berlin (CSB), 10117 Berlin, Germany.
Neuroscience. 2019 Sep 15;416:20-29. doi: 10.1016/j.neuroscience.2019.07.032. Epub 2019 Jul 26.
In the adult hippocampal dentate gyrus (DG), the majority of newly generated cells are eliminated by apoptotic mechanisms. The apoptosis repressor with caspase recruitment domain (ARC), encoded by the Nol3 gene, is a potent and multifunctional death repressor that inhibits both death receptor and mitochondrial apoptotic signaling. The aim of the present study was to parse the role of ARC in the development of new granule cell neurons. Nol3 gene expression as revealed by in situ hybridization is present in the entire dentate granule cell layer. Moreover, a comparison of Nol3 expression between FACS-sorted Sox2-positive neural stem cells and Doublecortin (DCX)-positive immature neurons demonstrates upregulation of Nol3 during neurogenesis. Using ARC-deficient mice, we show that proliferation and survival of BrdU birth-dated cells are strongly reduced in the absence of ARC while neuronal-glial fate choice is not affected. Both the number of DCX-positive cells and the number of calretinin (CR)-positive immature postmitotic neurons are reduced in the hippocampus of ARC mice. ARC knockout is not associated with increased numbers of microglia or with microglia activation. However, hippocampal brain-derived neurotrophic factor (BDNF) protein content is significantly increased in ARC mice, possibly representing a compensatory response. Collectively, our results suggest that ARC plays a critical cell-autonomous role in preventing cell death during adult granule cell neogenesis.
在成年海马齿状回（DG）中，大多数新生成的细胞通过凋亡机制被消除。凋亡抑制剂与半胱氨酸蛋白酶募集域（ARC），由 Nol3 基因编码，是一种有效的多功能死亡抑制剂，可抑制死亡受体和线粒体凋亡信号。本研究的目的是解析 ARC 在新颗粒细胞神经元发育中的作用。原位杂交显示 Nol3 基因表达存在于整个齿状回颗粒细胞层中。此外，比较 FACS 分选的 Sox2 阳性神经干细胞和 Doublecortin（DCX）阳性未成熟神经元之间的 Nol3 表达表明，在神经发生过程中 Nol3 上调。使用 ARC 缺陷小鼠，我们发现 ARC 缺失会强烈降低 BrdU 出生标记细胞的增殖和存活，而神经元-神经胶质命运选择不受影响。在 ARC 小鼠的海马体中，DCX 阳性细胞的数量和 calretinin（CR）阳性未成熟有丝分裂后神经元的数量均减少。ARC 敲除与小胶质细胞数量增加或小胶质细胞激活无关。然而，ARC 小鼠的海马脑源性神经营养因子（BDNF）蛋白含量显著增加，可能代表一种代偿反应。总之，我们的结果表明，ARC 在防止成年颗粒细胞新生过程中的细胞死亡中发挥着关键的细胞自主作用。
