Deficiency of MicroRNA-23-27-24 Clusters Exhibits the Impairment of Myelination in the Central Nervous System.

IF 3 4区 医学 Q2 NEUROSCIENCES
Yuji Tsuchikawa, Naosuke Kamei, Yohei Sanada, Toshio Nakamae, Takahiro Harada, Kazunori Imaizumi, Takayuki Akimoto, Shigeru Miyaki, Nobuo Adachi
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Abstract

Several microRNAs (miRNAs), including miR-23 and miR-27a have been reportedly involved in regulating myelination in the central nervous system. Although miR-23 and miR-27a form clusters in vivo and the clustered miRNAs are known to perform complementary functions, the role of these miRNA clusters in myelination has not been studied. To investigate the role of miR-23-27-24 clusters in myelination, we generated miR-23-27-24 cluster knockout mice and evaluated myelination in the brain and spinal cord. Our results showed that 10-week-old knockout mice had reduced motor function in the hanging wire test compared to the wild-type mice. At 4 weeks, 10 weeks, and 12 months of age, knockout mice showed reduced myelination compared to wild-type mice. The expression levels of myelin basic protein and myelin proteolipid protein were also significantly lower in the knockout mice compared to the wild-type mice. Although differentiation of oligodendrocyte progenitor cells to oligodendrocytes was not inhibited in the knockout mice, the percentage of oligodendrocytes expressing myelin basic protein was significantly lower in 4-week-old knockout mice than that in wild-type mice. Proteome analysis and western blotting showed increased expression of leucine-zipper-like transcription regulator 1 (LZTR1) and decreased expression of R-RAS and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) in the knockout mice. In summary, loss of miR-23-27-24 clusters reduces myelination and compromises motor functions in mice. Further, LZTR1, which regulates R-RAS upstream of the ERK1/2 pathway, a signal that promotes myelination, has been identified as a novel target of the miR-23-27-24 cluster in this study.

Abstract Image

Abstract Image

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MicroRNA-23-27-24簇缺乏表现出中枢神经系统髓鞘形成的损伤。
据报道,包括miR-23和miR-27a在内的几种microrna (mirna)参与调节中枢神经系统的髓鞘形成。尽管miR-23和miR-27a在体内形成簇,并且已知簇状miRNA具有互补功能,但这些miRNA簇在髓鞘形成中的作用尚未被研究。为了研究miR-23-27-24簇在髓鞘形成中的作用,我们产生了miR-23-27-24簇敲除小鼠,并评估了脑和脊髓的髓鞘形成。我们的研究结果显示,与野生型小鼠相比,10周大的基因敲除小鼠在吊丝试验中的运动功能有所降低。在4周、10周和12个月大时,与野生型小鼠相比,基因敲除小鼠的髓鞘形成减少。与野生型小鼠相比,敲除小鼠的髓磷脂碱性蛋白和髓磷脂蛋白的表达水平也显著降低。虽然基因敲除小鼠少突胶质细胞祖细胞向少突胶质细胞的分化并未受到抑制,但4周龄基因敲除小鼠表达髓鞘碱性蛋白的少突胶质细胞比例明显低于野生型小鼠。蛋白质组学分析和western blotting显示,敲除小鼠中亮氨酸拉链样转录调节因子1 (LZTR1)的表达增加,R-RAS和磷酸化细胞外信号调节激酶1/2 (pERK1/2)的表达降低。总之,miR-23-27-24簇的缺失减少了小鼠的髓鞘形成并损害了运动功能。此外,LZTR1调节ERK1/2通路上游的R-RAS,这是一种促进髓鞘形成的信号,在本研究中已被确定为miR-23-27-24簇的新靶点。
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来源期刊
Neural Plasticity
Neural Plasticity NEUROSCIENCES-
CiteScore
6.80
自引率
0.00%
发文量
77
审稿时长
16 weeks
期刊介绍: Neural Plasticity is an international, interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology. Neural Plasticity publishes research and review articles from the entire range of relevant disciplines, including basic neuroscience, behavioral neuroscience, cognitive neuroscience, biological psychology, and biological psychiatry.
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