Department of Molecular Neuroscience, College of Medicine, Dong-A University, Busan 602-714, Korea.
School of Medicine, Pusan National University, Yangsan 50612, Korea.
Int J Mol Sci. 2021 Oct 27;22(21):11601. doi: 10.3390/ijms222111601.
Although microRNAs (miRNAs or miRs) have been studied in the peripheral nervous system, their function in Schwann cells remains elusive. In this study, we performed a microRNA array analysis of cyclic adenosine monophosphate (cAMP)-induced differentiated primary Schwann cells. pathway enrichment analysis of the target genes showed that upregulated miRNAs (mR212-5p, miR335, miR20b-5p, miR146b-3p, and miR363-5p) were related to the calcium signaling pathway, regulation of actin cytoskeleton, retrograde endocannabinoid signaling, and central carbon metabolism in cancer. Several key factors, such as purinergic receptors (P2X), guanine nucleotide-binding protein G(olf) subunit alpha (GNAL), P2RX5, P2RX3, platelet-derived growth factor receptor alpha (PDGFRA), and inositol 1,4,5-trisphosphate receptor type 2 (ITPR2; calcium signaling pathway) are potential targets of miRNAs regulating cAMP. Our analysis revealed that miRNAs were differentially expressed in cAMP-treated Schwann cells; miRNA363-5p was upregulated and directly targeted the P2X purinoceptor 4 (P2RX4)-UTR, reducing the luciferase activity of P2RX4. The expression of miRNA363-5p was inhibited and the expression of P2RX4 was upregulated in sciatic nerve injury. In contrast, miRNA363-5p expression was upregulated and P2RX4 expression was downregulated during postnatal development. Of note, a P2RX4 antagonist counteracted myelin degradation after nerve injury and increased pERK and c-Jun expression. Interestingly, a P2RX4 antagonist increased the levels of miRNA363-5p. This study suggests that a double-negative feedback loop between miRNA363-5p and P2RX4 contributes to the dedifferentiation and migration of Schwann cells after nerve injury.
尽管 microRNAs（miRNAs 或 miRs）在周围神经系统中已有研究，但它们在 Schwann 细胞中的功能仍不明确。在本研究中，我们对环磷酸腺苷（cAMP）诱导分化的原代 Schwann 细胞进行了 microRNA 阵列分析。靶基因的通路富集分析表明，上调的 miRNAs（mR212-5p、miR335、miR20b-5p、miR146b-3p 和 miR363-5p）与钙信号通路、肌动蛋白细胞骨架调节、逆行内源性大麻素信号和癌症中的中心碳代谢有关。几个关键因子，如嘌呤能受体（P2X）、鸟嘌呤核苷酸结合蛋白 G（olf）亚基α（GNAL）、P2RX5、P2RX3、血小板衍生生长因子受体α（PDGFRA）和肌醇 1,4,5-三磷酸受体 2（ITPR2；钙信号通路）是调节 cAMP 的 miRNAs 的潜在靶标。我们的分析表明，miRNAs 在 cAMP 处理的 Schwann 细胞中差异表达；miRNA363-5p 上调，并直接靶向 P2X 嘌呤能受体 4（P2RX4）-UTR，降低 P2RX4 的荧光素酶活性。在坐骨神经损伤中，miRNA363-5p 的表达受到抑制，P2RX4 的表达上调。相反，在出生后发育过程中，miRNA363-5p 的表达上调，P2RX4 的表达下调。值得注意的是，P2RX4 拮抗剂在神经损伤后可拮抗髓鞘降解并增加 pERK 和 c-Jun 的表达。有趣的是，P2RX4 拮抗剂增加了 miRNA363-5p 的水平。本研究表明，miRNA363-5p 和 P2RX4 之间的负反馈环有助于神经损伤后 Schwann 细胞的去分化和迁移。
