The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats
The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats
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长非编码 RNA Arrl1 在大鼠神经元再生过程中作为竞争性内源性 RNA 抑制神经突生长
DOI：
10.1074/jbc.ra119.011917
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发表时间：
2020-06-19
影响因子：
4.8
通讯作者：
Yu, Bin
中科院分区：
文献类型：
--
作者：
Wang, Dong;Chen, Yanping;Yu, Bin
神经元的内在再生能力是周围神经损伤修复的关键因素。因此，明确神经再生的关键调控因子有助于促进轴突再生和损伤后的功能恢复。与经典的转录因子和再生相关基因不同，长非编码RNA(LncRNAs)在神经元再生调控中的功能仍不清楚。在这项研究中，我们使用基于RNA-Seq的转录组图谱来分析坐骨神经损伤后大鼠背根神经节(DRG)中lncRNAs和mRNAs的表达模式。使用lncRNA-mRNA共表达网络、基因本体丰富和京都百科全书基因和基因组途径数据库的分析表明，lncRNA Arrl1减少了神经元损伤后的突起生长。ShRNA介导的Arrl1沉默促进了体外和体内轴突的再生，并改善了坐骨神经的功能恢复。此外，抑制Arrl1的靶基因--细胞周期蛋白依赖性激酶抑制物2B(CDKN2B)，可显著促进DRG神经元突起的生长。我们还发现Arrl1作为竞争的内源RNA，海绵CDKN2B抑制子microRNA-761(miR-761)，从而在神经元再生过程中上调CDKN2B的表达。我们认为，lncRNA Arrl1通过下调CDKN2B的表达来影响DRG神经元的内源性再生。我们的研究结果表明，在大鼠周围神经损伤后，lncRNA-microRNA-Kinase通路在轴突再生和功能恢复中起着调节作用。
The intrinsic regeneration ability of neurons is a pivotal factor in the repair of peripheral nerve injury. Therefore, identifying the key modulators of nerve regeneration may help improve axon regeneration and functional recovery after injury. Unlike for classical transcription factors and regeneration-associated genes, the function of long noncoding RNAs (lncRNAs) in the regulation of neuronal regeneration remains mostly unknown. In this study, we used RNA-Seq–based transcriptome profiling to analyze the expression patterns of lncRNAs and mRNAs in rat dorsal root ganglion (DRG) following sciatic nerve injury. Analyses using the lncRNA-mRNA co-expression network, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway databases indicated that the lncRNA Arrl1 decreases neurite outgrowth after neuronal injury. shRNA-mediated Arrl1 silencing increased axon regeneration both in vitro and in vivo and improved functional recovery of the sciatic nerve. Moreover, inhibiting an identified target gene of Arrl1, cyclin-dependent kinase inhibitor 2B (Cdkn2b), markedly promoted neurite outgrowth of DRG neurons. We also found that Arrl1 acts as a competing endogenous RNA that sponges a Cdkn2b repressor, microRNA-761 (miR-761), and thereby up-regulates Cdkn2b expression during neuron regeneration. We conclude that the lncRNA Arrl1 affects the intrinsic regeneration of DRG neurons by derepressing Cdkn2b expression. Our findings indicate a role for an lncRNA-microRNA-kinase pathway in the regulation of axon regeneration and functional recovery following peripheral nerve injury in rats.