Long non-coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells.
Long non-coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells.
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长非编码 RNA Malat1 通过激活 N2a 细胞中的 ERK/MAPK 信号通路促进神经突生长
DOI：
10.1111/jcmm.12904
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发表时间：
2016-11
影响因子：
5.3
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Chen L;Feng P;Zhu X;He S;Duan J;Zhou D
越来越多的证据表明，长链非编码rna （lncRNAs）在神经发生中起着关键作用，但其潜在的分子机制仍然难以捉摸。神经突的生长是神经元分化和再生的早期步骤。以神经母细胞瘤衍生的Neuro - 2a （N2a）细胞的体外分化为模型，我们进行了表达谱分析，以确定与神经突生长相关的lncrna。我们发现转移相关肺腺癌转录本1 （Malat1）是N2a细胞分化过程中最显著上调的lncrna之一。Malat1敲低导致神经突生长缺陷以及细胞死亡增加。为了精确定位受Malat1缺失干扰的信号通路，我们随后进行了基于报告因子的筛选，以检查Malat1敲低细胞中50个信号通路的活性。我们发现Malat1敲低导致丝裂原活化蛋白激酶（MAPK）信号通路的明显抑制以及过氧化物酶体增殖物活化受体（PPAR）和P53信号通路的异常激活。PD98059抑制ERK/MAPK通路可有效阻断N2a细胞的神经突生长，而phorbol 12 -肉豆蔻酸13 -醋酸盐诱导的ERK激活可挽救由Malat1耗竭引起的神经突生长缺陷和细胞死亡。总之，我们的研究结果确定了Malat1通过激活ERK/MAPK信号通路在神经元分化的早期阶段发挥关键作用。
Accumulating evidence suggests that long non‐coding RNAs (lncRNAs) are playing critical roles in neurogenesis, yet the underlying molecular mechanisms remain largely elusive. Neurite outgrowth is an early step in neuronal differentiation and regeneration. Using in vitro differentiation of neuroblastoma‐derived Neuro‐2a (N2a) cell as a model, we performed expression profiling to identify lncRNAs putatively relevant for neurite outgrowth. We identified that Metastasis‐associated lung adenocarcinoma transcript 1 (Malat1) was one of the most significantly up‐regulated lncRNAs during N2a cell differentiation. Malat1 knockdown resulted in defects in neurite outgrowth as well as enhanced cell death. To pinpoint signalling pathways perturbed by Malat1 depletion, we then performed a reporter‐based screening to examine the activities of 50 signalling pathways in Malat1 knockdown cells. We found that Malat1 knockdown resulted in conspicuous inhibition of Mitogen‐Activated Protein Kinase (MAPK) signaling pathway as well as abnormal activation of Peroxisome proliferator‐activated receptor (PPAR) and P53 signalling pathway. Inhibition of ERK/MAPK pathway with PD98059 potently blocked N2a cell neurite outgrowth, whereas phorbol 12‐myristate 13‐acetate‐induced ERK activation rescued defects in neurite outgrowth and cell death induced by Malat1 depletion. Together, our results established a critical role of Malat1 in the early step of neuronal differentiation through activating ERK/MAPK signalling pathway.
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影响因子：
7.7
作者：
Sauvageau M;Goff LA;Lodato S;Bonev B;Groff AF;Gerhardinger C;Sanchez-Gomez DB;Hacisuleyman E;Li E;Spence M;Liapis SC;Mallard W;Morse M;Swerdel MR;D'Ecclessis MF;Moore JC;Lai V;Gong G;Yancopoulos GD;Frendewey D;Kellis M;Hart RP;Valenzuela DM;Arlotta P;Rinn JL
通讯作者：
Rinn JL
影响因子：
4.5
作者：
Tripathi V;Shen Z;Chakraborty A;Giri S;Freier SM;Wu X;Zhang Y;Gorospe M;Prasanth SG;Lal A;Prasanth KV
通讯作者：
Prasanth KV
影响因子：
4.8
作者：
Mao, AJ;Bechberger, J;Naus, CCG
通讯作者：
Naus, CCG
影响因子：
10.5
作者：
Dey BK;Pfeifer K;Dutta A
通讯作者：
Dutta A
影响因子：
7.7
作者：
Chalei V;Sansom SN;Kong L;Lee S;Montiel JF;Vance KW;Ponting CP
通讯作者：
Ponting CP