A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila.
A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila.
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DOI：
10.1371/journal.pgen.1006247
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发表时间：
2016-08
期刊：
影响因子：
4.5
通讯作者：
Sokol NS
中科院分区：
文献类型：
--
作者：
Chawla G;Deosthale P;Childress S;Wu YC;Sokol NS
信使RNA(MRNAs)通常包含多个不同的microRNAs(MiRNAs)的结合位点。然而，这一特征的生物学意义尚不清楚，因为这种共同靶向的miRNAs可以相互协调、独立或冗余地发挥作用。在这里，我们证明了两个共转录的果蝇miRNAs，let-7和miR-125，非冗余地调节一个共同的靶标，转录因子时间上不适当的形态发生(Chinmo)。我们首先表征了与let-7和miR-125丢失相关的新的成体表型，这两种表型来自一个常见的多顺反子转录本，该转录本还编码第三个miRNA，miR-100。与衰老果蝇中所有三个miRNAs的协同上调一致，这些表型包括大脑退化和寿命缩短。然而，转基因挽救分析揭示了这些miRNAs的单独作用：成人miR-125而不是let-7突变表型与成人大脑中异位的Chinmo表达有关，并被chinmo还原抑制。相反，let-7主要负责调节神经系统形成过程中的chinmo。这些结果表明，let-7和miR-125在发育和成年期两个不同的阶段发挥作用，而不是同时发挥作用。这些不同的活动是由于LET-7在发育过程中处理速度的增加和成人神经系统中积累的miR-125的较低衰减率而促进的。因此，这项工作不仅为高度保守的miR-125在衰老过程中发挥了关键作用。它还表明，两个共转录的miRNAs在不同的阶段独立发挥功能，调节一个共同的靶标，这增加了这样的双相控制可能是集群miRNAs的一般特征的可能性。多个miRNAs靶向的mRNAs的去调控是包括神经退行性疾病在内的许多疾病状态的共同特征。目前被接受的模型是，所有结合的miRNAs的联合作用确保靶向抑制。在这里，我们证明了两个共同表达的miRNAs在共同的靶点上发挥着不同的结果。虽然miR-125通过在成人大脑中抑制其靶点chinmo来延长寿命，但let-7在发育中的动物中下调了chinmo的表达。我们的结果表明，let-7和miR-125的不同加工和周转速度有助于miRNA活性的这种转换。本研究确定了在每个miRNA产生不同且不重叠的结果的情况下，多个miRNAs靶向单个mRNAs的生理相关性。
Messenger RNAs (mRNAs) often contain binding sites for multiple, different microRNAs (miRNAs). However, the biological significance of this feature is unclear, since such co-targeting miRNAs could function coordinately, independently, or redundantly with one another. Here, we show that two co-transcribed Drosophila miRNAs, let-7 and miR-125, non-redundantly regulate a common target, the transcription factor Chronologically Inappropriate Morphogenesis (Chinmo). We first characterize novel adult phenotypes associated with loss of both let-7 and miR-125, which are derived from a common, polycistronic transcript that also encodes a third miRNA, miR-100. Consistent with the coordinate upregulation of all three miRNAs in aging flies, these phenotypes include brain degeneration and shortened lifespan. However, transgenic rescue analysis reveal separable roles for these miRNAs: adult miR-125 but not let-7 mutant phenotypes are associated with ectopic Chinmo expression in adult brains and are suppressed by chinmo reduction. In contrast, let-7 is predominantly responsible for regulating chinmo during nervous system formation. These results indicate that let-7 and miR-125 function during two distinct stages, development and adulthood, rather than acting at the same time. These different activities are facilitated by an increased rate of processing of let-7 during development and a lower rate of decay of the accumulated miR-125 in the adult nervous system. Thus, this work not only establishes a key role for the highly conserved miR-125 in aging. It also demonstrates that two co-transcribed miRNAs function independently during distinct stages to regulate a common target, raising the possibility that such biphasic control may be a general feature of clustered miRNAs. Deregulation of mRNAs that are targeted by multiple miRNAs is a common feature of a number of diseased states including neurodegenerative disorders. The currently accepted model is that the combined action of all binding miRNAs ensures target repression. Here, we show that two co-expressed miRNAs exert distinct outcomes on a common target. While miR-125 extends lifespan by repressing its target, chinmo, in adult brains, let-7 downregulates Chinmo in developing animals. Our results indicate that differential processing and turnover rates of let-7 and miR-125 contribute to this switch in miRNA activity. This study has identified the physiological relevance of the targeting of a single mRNA by multiple miRNAs in a scenario where each miRNA exerts a distinct and non-overlapping outcome.