miR-221 and miR-222 promote Schwann cell proliferation and migration by targeting LASS2 after sciatic nerve injury
miR-221 and miR-222 promote Schwann cell proliferation and migration by targeting LASS2 after sciatic nerve injury
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DOI：
10.1242/jcs.098996
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发表时间：
2012-06
影响因子：
4
通讯作者：
Bin Yu;Songlin Zhou;Yongjun Wang;Tianmei Qian;Guohui Ding;F. Ding;X. Gu
中科院分区：
文献类型：
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作者：
Bin Yu;Songlin Zhou;Yongjun Wang;Tianmei Qian;Guohui Ding;F. Ding;X. Gu
microRNA（miRNAs）是一类在转录后水平调控基因表达的非编码小RNA。它们在调节雪旺细胞（SC）对损伤刺激的反应中的作用尚未被探索。在这里，我们报告了动态变化的miRNA表达大鼠坐骨神经损伤后，使用微阵列分析。我们收集了近端神经残端，并鉴定了77种在神经切断后四个时间点显示显著变化的miRNA。随后，我们分析了miRNA的表达模式，选择了一个显着的配置文件，然后整合推定的miRNA目标与差异表达的mRNA产生274个潜在的目标。这274个靶点主要涉及细胞增殖、细胞运动和细胞稳态，已知这些靶点在调节细胞表型中起重要作用。发现miR-221和miR-222簇（miR-221/222）的上调与损伤诱导的SC表型调节相关。miR-221/222的表达增强可促进SC的体外增殖和迁移，而沉默其表达则导致增殖和迁移减少。进一步的研究表明，长寿保证同源物2（LASS 2）是miR-221/222在SC中的直接靶点，因为miR-221/222直接结合LASS 2的3′-非翻译区，从而降低LASS 2的mRNA和蛋白水平。LASS 2的沉默重现了miR-221/222模拟物的作用，而LASS 2的强制敲除逆转了miR-221/222抑制剂的抑制作用。我们的研究结果表明，损伤通过靶向LASS 2调节miR-221/222促进SC增殖和迁移，并为miRNAs在神经再生中的作用提供了新的见解。
microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Their roles in regulating the responses of Schwann cells (SCs) to injury stimuli remain unexplored. Here we report dynamic alteration of miRNA expression following rat sciatic nerve injury using microarray analysis. We harvested the proximal nerve stumps and identified 77 miRNAs that showed significant changes at four time points after nerve transection. Subsequently, we analyzed the expression pattern of miRNA, selected one significant profile, and then integrated putative miRNA targets with differentially expressed mRNA yielding 274 potential targets. The 274 targets were mainly involved in cell proliferation, cell locomotion and cellular homeostasis that were known to play important roles in modulating cell phenotype. The upregulation of the miR-221 and miR-222 cluster (miR-221/222) was found to correlate with the injury-induced SC phenotypic modulation. Enhanced expression of miR-221/222 could promote SC proliferation and migration in vitro, whereas silencing their expression resulted in a reduced proliferation and migration. Further studies revealed that longevity assurance homologue 2 (LASS2) was a direct target of miR-221/222 in SCs because miR-221/222 bound directly to the 3′-untranslated region of LASS2, thus reducing both mRNA and protein levels of LASS2. Silencing of LASS2 recapitulated the effects of miR-221/222 mimics, whereas enforced knockdown of LASS2 reversed the suppressive effects of miR-221/222 inhibitors. Our findings indicate that injury promotes SC proliferation and migration through the regulation of miR-221/222 by targeting LASS2, and provide new insights into the role of miRNAs in nerve regeneration.