miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models.
miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models.
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DOI：
10.1038/s41467-018-04892-4
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发表时间：
2018-06-26
影响因子：
16.6
通讯作者：
Artero R
中科院分区：
文献类型：
--
作者：
Cerro-Herreros E;Sabater-Arcis M;Fernandez-Costa JM;Moreno N;Perez-Alonso M;Llamusi B;Artero R
选择性剪接因子Muscleblind-like（MBNL 1和2）的功能缺失是神经肌肉疾病强直性肌营养不良1型（DM 1）的基础。我们先前在果蝇DM 1模型中显示了miRNA下调的功效。在这里，我们筛选在HeLa细胞中调节MBNL 1和MBNL 2的miRNA。因此，我们鉴定了miR-23 b和miR-218，并证实它们在该细胞系中下调MBNL蛋白。miR-23 b和miR-218 miRNA的拮抗剂增强DM 1成肌细胞中MBNL蛋白水平并挽救致病性错剪接事件。全身递送这些“HSALR miR”类似地促进MBNL表达并改善DM 1样表型，包括HSALR DM 1模型小鼠中的剪接改变、组织病理学和肌强直。这些哺乳动物数据为治疗性阻断控制强直性肌营养不良中肌盲样蛋白表达的miRNA提供了证据。剪接因子MBNL 1和2的耗尽导致强直性肌营养不良。在这里，作者表明miR-23 b和miR-218靶向MBNL蛋白，并且这些miRNA的拮抗剂在小鼠模型中挽救成肌细胞中的错误剪接事件并促进MBNL表达和挽救病理学。
Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells. We thus identify miR-23b and miR-218, and confirm that they downregulate MBNL proteins in this cell line. Antagonists of miR-23b and miR-218 miRNAs enhance MBNL protein levels and rescue pathogenic missplicing events in DM1 myoblasts. Systemic delivery of these “antagomiRs” similarly boost MBNL expression and improve DM1-like phenotypes, including splicing alterations, histopathology, and myotonia in the HSALR DM1 model mice. These mammalian data provide evidence for therapeutic blocking of the miRNAs that control Muscleblind-like protein expression in myotonic dystrophy. Depletion of the splicing factors MBNL 1 and 2 causes myotonic dystrophy. Here, the authors show that miR-23b and miR-218 target MBNL proteins, and that antagonists to these miRNAs rescue mis-splicing events in myoblasts and boost MBNL expression and rescue pathology in mouse models.
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影响因子：
4.6
作者：
Chen G;Masuda A;Konishi H;Ohkawara B;Ito M;Kinoshita M;Kiyama H;Matsuura T;Ohno K
通讯作者：
Ohno K
影响因子：
4
作者：
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影响因子：
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通讯作者：
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影响因子：
10.5
作者：
Dey, Bijan K.;Gagan, Jeffrey;Dutta, Anindya
通讯作者：
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影响因子：
4.3
作者：
Bargiela A;Cerro-Herreros E;Fernandez-Costa JM;Vilchez JJ;Llamusi B;Artero R
通讯作者：
Artero R