Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON L5L 1C6, Canada.
Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada.
Sci Rep. 2018 Mar 28;8(1):5294. doi: 10.1038/s41598-018-23673-z.
Adult hippocampal neurogenesis is highly responsive to exercise, which promotes the proliferation of neural progenitor cells and the integration of newborn granule neurons in the dentate gyrus. Here we show that genetic ablation of the small GTPase, Dexras1, suppresses exercise-induced proliferation of neural progenitors, alters survival of mitotic and post-mitotic cells in a stage-specific manner, and increases the number of mature newborn granule neurons. Dexras1 is required for exercise-triggered recruitment of quiescent neural progenitors into the cell cycle. Pharmacological inhibition of NMDA receptors enhances SGZ cell proliferation in wild-type but not dexras1-deficient mice, suggesting that NMDA receptor-mediated signaling is dependent on Dexras1. At the molecular level, the absence of Dexras1 abolishes exercise-dependent activation of ERK/MAPK and CREB, and inhibits the upregulation of NMDA receptor subunit NR2A, bdnf, trkB and vegf-a expression in the dentate gyrus. Our study reveals Dexras1 as an important stage-specific regulator of exercise-induced neurogenesis in the adult hippocampus by enhancing pro-mitogenic signaling to neural progenitor cells and modulating cell survival.
成年海马神经发生对运动高度敏感，运动促进神经祖细胞的增殖和新生颗粒神经元在齿状回的整合。在这里，我们表明小 GTPase Dexras1 的基因缺失抑制了运动诱导的神经祖细胞增殖，以特定于阶段的方式改变有丝分裂和有丝分裂后细胞的存活，并增加成熟新生颗粒神经元的数量。Dexras1 是运动触发静止神经祖细胞进入细胞周期所必需的。NMDA 受体的药理学抑制增强了野生型但不是 dexras1 缺陷型小鼠 SGZ 细胞的增殖，表明 NMDA 受体介导的信号依赖于 Dexras1。在分子水平上，Dexras1 的缺失消除了运动依赖性 ERK/MAPK 和 CREB 的激活，并抑制了齿状回中 NMDA 受体亚基 NR2A、bdnf、trkB 和 vegf-a 表达的上调。我们的研究揭示了 Dexras1 作为成年海马体中运动诱导神经发生的一个重要的特定阶段调节因子，通过增强向神经祖细胞的促有丝分裂信号和调节细胞存活来发挥作用。
