Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy
Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy
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DOI：
10.1093/hmg/ddl132
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发表时间：
2006-07-01
影响因子：
3.5
通讯作者：
Thornton, Charles A.
中科院分区：
文献类型：
--
作者：
Lin, Xiaoyan;Miller, Jill W.;Thornton, Charles A.
在强直性肌营养不良（DM）中，含有扩增的CUG或CCUG重复序列的RNA的表达导致前体mRNA的错误调节的选择性剪接。携带重复的转录物与肌盲家族中的蛋白质MBNL1和MBNL2一起积累在核灶中。在表达扩展CUG重复序列的转基因小鼠中，我们发现剪接缺陷选择性地靶向一组外显子，这些外显子具有共同的发育调控时间模式。这些外显子在野生型小鼠出生后第2天和第20天之间进行同步剪接转换。在此出生后的间隔，MBNL1蛋白易位从主要的细胞质到核分布。在没有MBNL1的情况下，这些生理剪接转换不会发生。在成熟肌纤维中由扩展的CUG重复序列诱导的剪接缺陷通过MBNL1的缺乏而不是通过MBNL2的缺乏而紧密地再现。在人类DM 1型和2型中存在类似的情况。MBNL1从肌肉核质中耗尽，因为在核灶中的隔离，并且相关的剪接缺陷与在MBNL1敲除小鼠中观察到的那些非常相似。这些结果表明，MBNL1通过控制发育调节剪接开关的关键集合参与骨骼肌的出生后重塑。MBNL1的隔离以及未能维持这些剪接转换在DM肌肉疾病的发病机制中具有关键作用。
In myotonic dystrophy (DM), expression of RNA containing expanded CUG or CCUG repeats leads to misregulated alternative splicing of pre-mRNA. The repeat-bearing transcripts accumulate in nuclear foci, together with proteins in the muscleblind family, MBNL1 and MBNL2. In transgenic mice that express expanded CUG repeats, we show that the splicing defect selectively targets a group of exons that share a common temporal pattern of developmental regulation. These exons undergo a synchronized splicing switch between post-natal day 2 and 20 in wild-type mice. During this post-natal interval, MBNL1 protein translocates from a predominantly cytoplasmic to nuclear distribution. In the absence of MBNL1, these physiological splicing transitions do not occur. The splicing defect induced by expanded CUG repeats in mature muscle fibers is closely reproduced by deficiency of MBNL1 but not by deficiency of MBNL2. A parallel situation exists in human DM type 1 and type 2. MBNL1 is depleted from the muscle nucleoplasm because of sequestration in nuclear foci, and the associated splicing defects are remarkably similar to those observed in MBNL1 knockout mice. These results indicate that MBNL1 participates in the post-natal remodeling of skeletal muscle by controlling a key set of developmentally regulated splicing switches. Sequestration of MBNL1, and failure to maintain these splicing transitions, has a pivotal role in the pathogenesis of muscle disease in DM.