Distal Alternative Last Exons Localize mRNAs to Neural Projections.
Distal Alternative Last Exons Localize mRNAs to Neural Projections.
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DOI：
10.1016/j.molcel.2016.01.020
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发表时间：
2016-03-17
期刊：
影响因子：
16
通讯作者：
Burge CB
中科院分区：
文献类型：
--
作者：
Taliaferro JM;Vidaki M;Oliveira R;Olson S;Zhan L;Saxena T;Wang ET;Graveley BR;Gertler FB;Swanson MS;Burge CB
mRNA在不同亚细胞位置的空间限制使得蛋白质的局部调节和合成成为可能。然而，mRNA定位的组织原则仍然知之甚少。在这里，我们分析了亚细胞转录组的神经投射和索马的原代小鼠皮层神经元和两个神经元细胞系，发现交替最后外显子（ALE）往往赋予异构体特异性定位。令人惊讶的是，基因远端ALE亚型是4倍更经常定位于神经突比基因近端亚型。在神经元分化过程中诱导局部亚型，并富集与肌盲样（Mbnl）家族RNA结合蛋白相关的基序。Mbnl 1和/或Mbnl 2的耗尽减少了数百种转录本的定位，暗示Mbnl参与mRNA向神经突的定位。我们提供的证据支持一个模型，在该模型中，ALE的基因组位置和亚细胞定位之间的联系，使协调诱导定位能力的mRNA亚型通过转录后调节程序，诱导分化过程中和逆转细胞重编程和癌症。
Spatial restriction of mRNA to distinct subcellular locations enables local regulation and synthesis of proteins. However, the organizing principles of mRNA localization remain poorly understood. Here, we analyzed subcellular transcriptomes of neural projections and soma of primary mouse cortical neurons and two neuronal cell lines and found that alternative last exons (ALEs) often confer isoform-specific localization. Surprisingly, gene-distal ALE isoforms were 4 times more often localized to neurites than gene-proximal isoforms. Localized isoforms were induced during neuronal differentiation and enriched for motifs associated with muscleblind-like (Mbnl) family RNA-binding proteins. Depletion of Mbnl1 and/or Mbnl2 reduced localization of hundreds of transcripts, implicating Mbnls in localization of mRNAs to neurites. We provide evidence supporting a model in which the linkage between genomic position of ALEs and subcellular localization enables coordinated induction of localization-competent mRNA isoforms through a post-transcriptional regulatory program that is induced during differentiation and reversed in cellular reprogramming and cancer.