Zhao Jianya, Han Jingling, Jiang Junkang, Shi Shangshi, Ma Xia, Liu Xinhang, Wang Cheng, Nie Xiaoke, He Yunhua, Jiang Shengyang, Wan Chunhua
Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Department of Occupational Medicine and Environmental Toxicity, School of Public Health, Nantong University, Nantong, Jiangsu Province, People's Republic of China.
Brain Res. 2015 Jul 30;1615:61-70. doi: 10.1016/j.brainres.2015.04.028. Epub 2015 Apr 24.
Zinc is an essential nutrient that is important for normal brain development. Zinc deficiency has been linked to aberrant neurological development and functioning. However, the molecular mechanisms underlying Zinc deficiency-induced neurological disorders remain largely elusive. In the present study, we showed that the proliferation of C17.2 neural stem cells (NSCs) was evidently impaired after exposed to low levels of Zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethy) ethylenediamine (TPEN). In addition, we found that TPEN-induced proliferative deficit of NSCs was related with significant downregulation of Wnt/β-catenin signaling. Zinc deficiency impaired the proliferation of neural stem cells in dose- and time-dependent manners. Western blot revealed that the levels of p-Ser9-glycogensynthase kinase-3β (p-GSK-3β) and β-catenin were remarkably downregulated during TPEN-induced C17.2 proliferative impairment. Moreover, immunofluorescent analysis indicated that the level of nuclear β-catenin was apparently decreased following TPEN exposure. Furthermore, application with GSK-3β inhibitor lithium chloride (LiCl) reversed TPEN-induced downregulation of β-catenin and impairment of cell proliferation. Flow cytometry analysis also showed that TPEN-induced impairment of NSC proliferation could be reversed by LiCl. Taken together, these findings suggested that the disturbance of canonical Wnt/β-catenin signaling pathway partially accounted for Zinc deficiency-induced proliferative impairment of NSCs.
锌是一种必需营养素，对正常的大脑发育至关重要。锌缺乏与异常的神经发育和功能有关。然而，锌缺乏诱导神经障碍的分子机制仍 largely 难以捉摸。在本研究中，我们表明，暴露于低水平的锌螯合剂 N,N,N',N'-四-(2-吡啶甲基)乙二胺(TPEN)后，C17.2 神经干细胞(NSCs)的增殖明显受损。此外，我们发现 TPEN 诱导的 NSCs 增殖缺陷与 Wnt/β-连环蛋白信号通路的显著下调有关。锌缺乏以剂量和时间依赖的方式损害神经干细胞的增殖。蛋白质印迹显示，在 TPEN 诱导的 C17.2 增殖损伤过程中，p-Ser9-糖原合酶激酶-3β(p-GSK-3β)和β-连环蛋白的水平显著下调。此外，免疫荧光分析表明，TPEN 暴露后核β-连环蛋白水平明显降低。此外，应用 GSK-3β抑制剂氯化锂(LiCl)可逆转 TPEN 诱导的β-连环蛋白下调和细胞增殖损伤。流式细胞术分析也表明，LiCl 可逆转 TPEN 诱导的 NSC 增殖损伤。综上所述，这些发现表明，经典 Wnt/β-连环蛋白信号通路的紊乱部分解释了锌缺乏诱导的 NSCs 增殖损伤。
