Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms
Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms
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DOI：
10.1016/j.brainres.2008.08.040
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发表时间：
2008-10-27
期刊：
影响因子：
2.9
通讯作者：
Levenson, Cathy W.
中科院分区：
文献类型：
--
作者：
Corniola, Rikki S.;Tassabehji, Nadine M.;Levenson, Cathy W.
干细胞在成人中枢神经系统(CNS)中的潜在重要性现在被广泛认识到，它不仅可以分裂，而且可以参与神经发生。虽然我们知道微量元素锌是大脑发育所必需的，但这种基本营养物质在成人干细胞增殖和神经发生中的作用还没有被研究过。与锌充足和配对喂养的对照组相比，喂养锌限制饮食的成年雄性大鼠在齿状回颗粒下带(SGZ)和颗粒细胞层中的Ki67阳性干细胞大致为SO/更少(p<；0.05)。与配对喂养的大鼠相比，缺锌大鼠SGZ内TUNEL标记细胞的数量也显著增加(p<；0.05)。为探讨缺锌的机制，用N，N，N‘，N’-四(2-吡啶甲基)乙二胺(TPEN)螯合剂去除培养的人NTERA-2(NT2)神经前体细胞中的锌。与体内缺乏的效果一致，TPEN处理导致细胞增殖显著下降，通过摄取溴脱氧尿苷(BrdU)来衡量，并增加依赖caspase3/7的细胞凋亡。伴随着这些变化的是核P53的增加。寡核苷酸阵列，再加上在NT2细胞中使用显性负向p53结构，鉴定出14个差异调控的p53靶基因。在缺锌的早期阶段，诱导了负责细胞周期停滞的P53靶点。持续的缺乏导致了多种促凋亡基因的诱导，如转化生长因子-β(TGF-β)和视网膜母细胞瘤-1(RB-1)，以及细胞保护基因如谷胱甘肽过氧化物酶(GPX)。这些数据表明，锌通过调节控制神经前体细胞增殖和存活的P53依赖的分子机制在神经发生中发挥作用。(C)2008爱思唯尔B.V.保留所有权利。
The potential importance of stem cells in the adult central nervous system (CNS) that cannot only divide, but also participate in neurogenesis, is now widely appreciated. While we know that the trace element zinc is needed for brain development, the role of this essential nutrient in adult stem cell proliferation and neurogenesis has not been investigated. Adult male rats fed a zinc-restricted diet had approximately SO/fewer Ki67-positive stem cells in the subgranular zone (SGZ) and granular cell layer of the dentate gyrus compared to both zinc-adequate and pair-fed controls (p < 0.05). Zinc-deficient rats also had a significant increase the number of TUNEL-labeled cells in the SGZ compared to pair-fed rats (p < 0.05). To explore the mechanisms responsible for the effects of zinc deficiency, cultured human Ntera-2 (NT2) neuronal precursor cells were deprived of zinc using the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Consistent with the effects of deficiency in vivo, TPEN treatment resulted in a significant decrease in cellular proliferation, as measured by bromodeoxyuridine (BrdU) uptake, and an increase in caspase3/7-dependent apoptosis. These changes were accompanied by increases in nuclear p53. Oligonucleotide arrays, coupled with use of a dominant-negative p53 construct in NT2 cells, identified 14 differentially regulated p53 target genes. In the early phases zinc deficiency, p53 targets responsible for cell cycle arrest were induced. Continuation of deficiency resulted in the induction of a variety of pro-apoptotic genes such as transforming growth factor-beta (TGF-beta) and retinoblastoma-1 (Rb-1), as well as cellular protection genes such as glutathione peroxidase (GPx). These data suggest that zinc plays a role in neurogenesis by regulating p53-dependent molecular mechanisms that control neuronal precursor cell proliferation and survival. (c) 2008 Elsevier B.V. All rights reserved.