Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function
Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function
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DOI：
10.1126/science.aam8526
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发表时间：
2017-09-22
期刊：
影响因子：
56.9
通讯作者：
Rajewsky, Nikolaus
中科院分区：
文献类型：
--
作者：
Piwecka, Monika;Glazar, Petar;Rajewsky, Nikolaus
哺乳动物脑中存在大量的环状RNA（circRNA），它们的表达通常是保守的。在这里，我们发现circRNA Cdr 1as在人类和小鼠大脑中被microRNA（miRNAs）miR-7和miR-671大量结合。当Cdr 1as位点从小鼠基因组中移除时，敲除的动物显示出受损的感觉运动门控（sensorimotor gating）--一种过滤不必要信息的能力缺陷--这与神经精神疾病有关。电生理记录显示突触传递功能障碍。miR-7和miR-671的表达在分析的所有脑区中特异性和转录后失调。在Cdr 1as缺陷的大脑中，立即早期基因（如Fos，一种直接的miR-7靶点）的表达增强，这为行为表型提供了可能的分子联系。我们的数据表明，在体内功能丧失的circRNA表型，并表明Cdr 1as和miRNA之间的相互作用是重要的正常脑功能。
Hundreds of circular RNAs (circRNAs) are highly abundant in the mammalian brain, often with conserved expression. Here we show that the circRNA Cdr1as is massively bound by the microRNAs (miRNAs) miR-7 and miR-671 in human and mouse brains. When the Cdr1as locus was removed from the mouse genome, knockout animals displayed impaired sensorimotor gating-a deficit in the ability to filter out unnecessary information-which is associated with neuropsychiatric disorders. Electrophysiological recordings revealed dysfunctional synaptic transmission. Expression of miR-7 and miR-671 was specifically and posttranscriptionally misregulated in all brain regions analyzed. Expression of immediate early genes such as Fos, a direct miR-7 target, was enhanced in Cdr1as-deficient brains, providing a possible molecular link to the behavioral phenotype. Our data indicate an in vivo loss-of-function circRNA phenotype and suggest that interactions between Cdr1as and miRNAs are important for normal brain function.