Ghibaudi Matilde, Boido Marina, Green Darrell, Signorino Elena, Berto Gaia Elena, Pourshayesteh Soraya, Singh Archana, Di Cunto Ferdinando, Dalmay Tamas, Vercelli Alessandro
Department of Neuroscience "Rita Levi Montalcini," Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Orbassano, Italy.
Polymers and Biomaterials, Italian Institute of Technology, Genova, Italy.
Front Mol Biosci. 2021 Mar 31;8:618869. doi: 10.3389/fmolb.2021.618869. eCollection 2021.
Spinal cord injury (SCI) affects 6 million people worldwide with no available treatment. Despite research advances, the inherent poor regeneration potential of the central nervous system remains a major hurdle. Small RNAs (sRNAs) 19-33 nucleotides in length are a set of non-coding RNA molecules that regulate gene expression and have emerged as key players in regulating cellular events occurring after SCI. Here we profiled a class of sRNA known as microRNAs (miRNAs) following SCI in the cortex where the cell bodies of corticospinal motor neurons are located. We identified miR-7b-3p as a candidate target given its significant upregulation after SCI and we screened by miRWalk PTM the genes predicted to be targets of miR-7b-3p (among which we identified , a gene regulating neurite extension). Moreover, 16 genes, involved in neural regeneration and potential miR-7b-3p targets, were found to be downregulated in the cortex following SCI. We also analysed miR-7b-3p function during cortical neuron development : we observed that the overexpression of miR-7b-3p was important (1) to maintain neurons in a more immature and, likely, plastic neuronal developmental phase and (2) to contrast the apoptotic pathway; however, in normal conditions it did not affect the Wipf2 expression. On the contrary, the overexpression of miR-7b-3p upon oxidative stress condition (mimicking the SCI environment) significantly reduced the expression level of Wipf2, as observed , confirming it as a direct miR-7b-3p target. Overall, these data suggest a dual role of miR-7b-3p: (i) the induction of a more plastic neuronal condition/phase, possibly at the expense of the axon growth, (ii) the neuroprotective role exerted through the inhibition of the apoptotic cascade. Increasing the miR-7b-3p levels in case of SCI could reactivate in adult neurons silenced developmental programmes, supporting at the same time the survival of the axotomised neurons.
脊髓损伤（SCI）影响着全球600万人，目前尚无有效治疗方法。尽管研究取得了进展，但中枢神经系统固有的再生能力差仍然是一个主要障碍。长度为19 - 33个核苷酸的小RNA（sRNAs）是一组非编码RNA分子，可调节基因表达，并已成为调节脊髓损伤后发生的细胞事件的关键因素。在这里，我们对皮质脊髓运动神经元细胞体所在的皮质中脊髓损伤后的一类称为微小RNA（miRNAs）的sRNA进行了分析。鉴于其在脊髓损伤后显著上调，我们将miR - 7b - 3p鉴定为候选靶点，并通过miRWalk PTM筛选了预测为miR - 7b - 3p靶点的基因（其中我们鉴定出一个调节神经突延伸的基因）。此外，发现16个参与神经再生且可能是miR - 7b - 3p靶点的基因在脊髓损伤后的皮质中表达下调。我们还分析了miR - 7b - 3p在皮质神经元发育过程中的功能：我们观察到miR - 7b - 3p的过表达很重要，一是将神经元维持在更不成熟且可能更具可塑性的神经元发育阶段，二是对抗细胞凋亡途径；然而，在正常条件下它不影响Wipf2的表达。相反，在氧化应激条件下（模拟脊髓损伤环境）miR - 7b - 3p的过表达显著降低了Wipf2的表达水平，如观察到的那样，证实它是miR - 7b - 3p的直接靶点。总体而言，这些数据表明miR - 7b - 3p具有双重作用：一是诱导更具可塑性的神经元状态/阶段，可能以轴突生长为代价；二是通过抑制凋亡级联反应发挥神经保护作用。在脊髓损伤的情况下增加miR - 7b - 3p的水平可能会重新激活成年神经元中沉默的发育程序，同时支持轴突切断的神经元的存活。
