...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Neuron >Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy
【24h】

Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy

机译：发育中的大脑和强直性营养不良中的失调的肌肉盲样2介导的选择性剪接。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program. Myotonic dystrophy, a disease caused by toxic RNAs, profoundly affects brain function. In this Article, Charizanis et al. demonstrate that the effect on brain function results from loss of muscleblind-like 2 RNA splicing regulation during brain development.
机译：强直性肌营养不良症（DM）的RNA介导的疾病模型提出微卫星C（C）TG扩展表达有毒RNA，通过改变MBNL1和CELF1活性来破坏剪接调控。虽然此模型解释了肌肉中的DM表现，但对C（C）UG表达对大脑的影响知之甚少。在这里，我们报告Mbnl2基因敲除小鼠发展几个DM相关的中枢神经系统（CNS）功能，包括异常的REM睡眠倾向和空间记忆缺陷。 Mbnl2在海马中显着表达，Mbnl2敲除表明NMDA受体（NMDAR）突触传递减少，海马突触可塑性受损。尽管Mbnl2的丢失并没有显着改变海马中的目标转录水平，但使用剪接微阵列，RNA-seq和HITS-CLIP检测到数百个外显子的剪接调节异常。重要的是，所检查的大多数受Mbnl2调节的外显子在DM中也受到类似的错误调节。我们建议DM脑的主要病理特征是由MBNL2介导的发育剪接程序的破坏引起的。强直性肌营养不良症（一种由毒性RNA引起的疾病）深刻影响着大脑的功能。在本文中，Charizanis等人。证明对大脑功能的影响是由于大脑发育过程中肌盲样2 RNA剪接调控的丧失。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号