Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy
Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy
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DOI：
10.1093/hmg/ddi162
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发表时间：
2005-06-01
影响因子：
3.5
通讯作者：
Cooper, TA
中科院分区：
文献类型：
--
作者：
Ho, TH;Bundman, D;Cooper, TA
强直性肌营养不良I型（DM 1）是由非编码CTG重复扩增引起的RNA介导的疾病。RNA介导的DM发病机制模型的一个关键特征是特异性前mRNA靶点的剪接被破坏。CUG-BP 1（CELF蛋白家族成员）的剪接调节与DM 1发病机制之间已经建立了联系。为了确定增加的CUG-BP 1功能是否足以模拟DM，产生了在心脏和骨骼肌（DM 1中受影响的两种组织）中过表达CUG-BP 1（MCKCUG-BP 1）的转基因小鼠。骨骼肌的组织学和电子显微镜分析揭示了DM组织的共同病理特征：中央核链、变性纤维和集中的NADH反应性。MCKCUG-BP 1小鼠破坏了三种CELF靶前mRNA的剪接，即心肌肌钙蛋白T（Tnnt 2）、肌微管蛋白相关1基因（Mtmr 1）和肌肉特异性氯离子通道（Clcn 1），这与在DM心脏和骨骼肌中观察到的一致。结果与DM发病机制一致，其中扩增的重复序列导致CUG-BP 1活性和/或其他CELF家族成员增加，并对特定的前mRNA靶标具有反式显性效应。
Myotonic dystrophy type I (DM1) is an RNA-mediated disease caused by a non-coding CTG repeat expansion. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. A link has been established between splicing regulation by CUG-BP1, a member of the CELF family of proteins, and DM1 pathogenesis. To determine whether increased CUG-BP1 function was sufficient to model DM, transgenic mice overexpressing CUG-BP1 (MCKCUG-BP1) in heart and skeletal muscle, two tissues affected in DM1, were generated. Histological and electron microscopic analyses of skeletal muscle reveal common pathological features with DM tissues: chains of central nuclei, degenerating fibers and centralized NADH reactivity. MCKCUG-BP1 mice have disrupted splicing of three CELF target pre-mRNAs, cardiac troponin T (Tnnt2), myotubularin-related 1 gene (Mtmr1) and the muscle-specific chloride channel (Clcn1), consistent with that observed in DM heart and skeletal muscle. The results are consistent with a mechanism for DM pathogenesis in which expanded repeats result in increased CUG-BP1 activity and/or other CELF family members and have trans-dominant effects on specific pre-mRNA targets.