The conserved microRNA MiR-8 tunes atrophin levels to prevent neurodegeneration in drosophila
The conserved microRNA MiR-8 tunes atrophin levels to prevent neurodegeneration in drosophila
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DOI：
10.1016/j.cell.2007.09.020
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发表时间：
2007-10-05
期刊：
影响因子：
64.5
通讯作者：
Cohen, Stephen M.
中科院分区：
文献类型：
--
作者：
Karres, Janina S.;Hilgers, Valerie;Cohen, Stephen M.
microRNAs（miRNAs）与特定的信使RNA靶点结合，在转录后调节其表达。理解miRNAs和靶点之间的调控关系仍然是一个重大挑战。许多miRNAs将其靶标的表达降低到无关紧要的水平。也有人提出，miRNAs可能会将靶标表达调节到最佳水平。在这里，我们分析了果蝇中保守的miRNA miR-8突变的后果。我们确定atrophin作为miR-8的直接靶点。miR-8突变表型可归因于升高的萎缩蛋白活性，导致脑中升高的细胞凋亡和行为缺陷。将表达miR-8的细胞中的萎缩蛋白水平降低至低于miR-8调节产生的水平是有害的，这为它们之间的“调节靶点”关系提供了证据。果蝇萎缩蛋白与哺乳动物转录调节因子的萎缩蛋白家族有关，与神经退行性疾病DRPLA有关。在哺乳动物中，miR-8和萎缩蛋白直系同源物之间的调节关系是保守的。
microRNAs ( miRNAs) bind to specific messenger RNA targets to posttranscriptionally modulate their expression. Understanding the regulatory relationships between miRNAs and targets remains a major challenge. Many miRNAs reduce expression of their targets to inconsequential levels. It has also been proposed that miRNAs might adjust target expression to an optimal level. Here we analyze the consequences of mutating the conserved miRNA miR-8 in Drosophila. We identify atrophin as a direct target of miR-8. miR-8 mutant phenotypes are attributable to elevated atrophin activity, resulting in elevated apoptosis in the brain and in behavioral defects. Reduction of atrophin levels in miR-8-expressing cells to below the level generated by miR-8 regulation is detrimental, providing evidence for a "tuning target'' relationship between them. Drosophila atrophin is related to the atrophin family of mammalian transcriptional regulators, implicated in the neurodegenerative disorderDRPLA. The regulatory relationship between miR-8 and atrophin orthologs is conserved in mammals.