IRES-mediated Wnt2 translation in apoptotic neurons triggers astrocyte dedifferentiation.
IRES-mediated Wnt2 translation in apoptotic neurons triggers astrocyte dedifferentiation.
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凋亡神经元中 IRES 介导的 Wnt2 翻译触发星形胶质细胞去分化
DOI：
10.1038/s41536-022-00248-1
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发表时间：
2022-09-02
影响因子：
7.2
通讯作者：
Wang, Yazhou
中科院分区：
文献类型：
--
作者：
Fan, Hong;Yang, Jialei;Zhang, Kun;Xing, Junling;Guo, Baolin;Mao, Honghui;Wang, Wenting;Hu, Yingzhou;Lin, Wei;Huang, Ying;Ding, Jian;Yu, Caiyong;Fu, Fanfan;Sun, Li;Wu, Jing;Zhao, Youyi;Deng, Wenbin;Zhou, Chengji;Qiu, Mengsheng;Wu, Shengxi;Ding, Yu-Qiang;Wang, Yazhou
反应性星形胶质细胞增生通常具有神经祖细胞的一些特性。损伤如何触发星形胶质细胞去分化仍不清楚。在此，我们报道了在小鼠、灵长类动物和人类中，缺血诱导凋亡神经元中Wnt2蛋白的快速上调和反应性星形细胞中典型Wnt信号的激活。局部递送Wnt2 shRNA可消除星形胶质细胞的去分化，而过表达Wnt2可促进祖细胞标志物的表达和神经发生。在缺血caspase-3−/−皮质中，Wnt信号的激活和星形胶质细胞的去分化均受到损害。过表达稳定的β-catenin不仅促进了缺血caspase-3−/−小鼠的神经发生，而且促进了功能恢复。进一步分析表明，凋亡神经元通过内部核糖体进入位点（IRES）介导的翻译上调Wnt2蛋白。敲低ires介导的蛋白翻译中的关键蛋白死亡相关蛋白5 (DAP5)，可显著降低Wnt激活和星形胶质细胞去分化。我们的数据表明，凋亡启动的wnt激活机制触发星形细胞去分化和促进神经元再生。
Reactive astrogliosis usually bears some properties of neural progenitors. How injury triggers astrocyte dedifferentiation remains largely unclear. Here, we report that ischemia induces rapid up-regulation of Wnt2 protein in apoptotic neurons and activation of canonical Wnt signaling in reactive astrocytes in mice, primates and human. Local delivery of Wnt2 shRNA abolished the dedifferentiation of astrocytes while over-expressing Wnt2 promoted progenitor marker expression and neurogenesis. Both the activation of Wnt signaling and dedifferentiation of astrocytes was compromised in ischemic caspase-3−/− cortex. Over-expressing stabilized β-catenin not only facilitated neurogenesis but also promoted functional recovery in ischemic caspase-3−/− mice. Further analysis showed that apoptotic neurons up-regulated Wnt2 protein via internal ribosome entry site (IRES)-mediated translation. Knocking down death associated protein 5 (DAP5), a key protein in IRES-mediated protein translation, significantly diminished Wnt activation and astrocyte dedifferentiation. Our data demonstrated an apoptosis-initiated Wnt-activating mechanism which triggers astrocytic dedifferentiation and facilitates neuronal regeneration.
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影响因子：
7.3
作者：
Li F;Huang Q;Chen J;Peng Y;Roop DR;Bedford JS;Li CY
通讯作者：
Li CY
耦合的增殖和凋亡维持成人大脑中小胶质细胞的快速离职。
影响因子：
8.8
作者：
Askew K;Li K;Olmos-Alonso A;Garcia-Moreno F;Liang Y;Richardson P;Tipton T;Chapman MA;Riecken K;Beccari S;Sierra A;Molnár Z;Cragg MS;Garaschuk O;Perry VH;Gomez-Nicola D
通讯作者：
Gomez-Nicola D
影响因子：
3.7
作者：
Fuerer C;Nusse R
通讯作者：
Nusse R
影响因子：
6.1
作者：
Kernie SG;Parent JM
通讯作者：
Parent JM
影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI