Gas5 inhibition promotes the axon regeneration in the adult mammalian nervous system
Gas5 inhibition promotes the axon regeneration in the adult mammalian nervous system
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Gas5 抑制促进成年哺乳动物神经系统的轴突再生
DOI：
10.1016/j.expneurol.2022.114157
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发表时间：
2022-07-14
影响因子：
5.3
通讯作者：
Zhou, Songlin
中科院分区：
文献类型：
--
作者：
Han, Xiaoxiao;Xu, Jiacheng;Zhou, Songlin
外周神经系统（PNS）中的神经元在轴突损伤后具有强大的再生能力，但哺乳动物的中枢神经系统（CNS）中的神经元通常不具有再生能力。越来越多的证据强调了长链非编码RNA（lncRNA）在发育和疾病中的关键作用，但LncRNA在触发CNS和PNS再生能力中的作用还没有得到很好的研究。在这里，我们报道了lncRNA Gas 5是轴突再生的抑制因子。生物信息学分析表明，Gas 5在DRG神经元发育过程中表达上调，在坐骨神经损伤后表达下调。在体外，抑制Gas 5的表达促进小鼠和大鼠DRG神经元的轴突生长。因此，Gas 5过表达抑制小鼠DRG神经元轴突生长。在体内，Gas 5基因敲除（Gas 5-/-）小鼠在坐骨神经损伤后表现出增强的神经再生能力。RNA pull-down分析表明Gas 5可以与周围神经发育和再生所必需的可溶性波形蛋白相互作用。波形蛋白敲低逆转Gas 5沉默调节的轴突促再生，表明Gas 5的功能依赖于波形蛋白。此外，抑制Gas 5表达还可以增强视神经再生，表明Gas 5沉默在CNS中具有潜在的促再生能力。我们的研究第一次提供了直接的证据，在体内lncRNA在调节中枢轴突再生的作用和Gas 5可能是一个新的治疗靶点轴突再生在PNS和CNS。
Neurons in the peripheral nervous system (PNS) have robust regenerative capacity after axon injury, but the regenerative capacity is generally absent in the neurons of the central nervous system (CNS) in mammals. Increasing evidence highlighted the pivotal roles of long-noncoding RNAs (lncRNAs) in development and disease, but the role of LncRNA in triggering the regenerative capacity in CNS and PNS is not well studied. Here, we reported that lncRNA Gas5 is a suppressor for axon regeneration. Bioinformatics analysis shows that Gas5 is agedependent up-regulated during DRG neurons development and down-regulated after sciatic nerve injury. In vitro, inhibiting the expression of Gas5 promotes the neurite growth of DRG neurons both in mice and rats. Consistently, Gas5 overexpression inhibits axon growth of mice DRG neurons. In vivo, Gas5 knockout(Gas5-/-) mice display enhanced nerve regeneration ability after sciatic nerve injury. RNA pull-down analysis indicates that Gas5 can interacts with soluble Vimentin, which is essential for peripheral nerve development and regeneration. Vimentin knockdown reverses the Gas5 silence-regulated axon pro-regeneration demonstrating that the function of Gas5 depending on Vimentin. Besides, inhibition of Gas5 expression can also enhance optic nerve regeneration indicating a potential pro-regenerative ability of Gas5 silence in CNS. Our study for the first time provides direct evidence in vivo that lncRNA plays a role in regulating central axon regrowth and Gas5 might be a novel therapeutic target for axon regeneration in both PNS and CNS.