Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function [miRNA-seq]

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. We performed miRNA sequencing for three knockout and three wild type replicates in four brain regions - cerebellum, cortex, hippocampus (2 KO replicates) and olfactory bulb.数百种环状RNA（circular RNAs, circRNAs）在哺乳动物大脑中高度富集，且其表达通常具有保守性。本研究证实，在人类与小鼠大脑中，环状RNA Cdr1as可大量结合微小RNA（microRNAs, miRNAs）miR-7与miR-671。当从小鼠基因组中敲除Cdr1as基因座后，基因敲除小鼠表现出感觉运动门控受损——即过滤冗余信息的能力存在缺陷，该表型与神经精神疾病密切相关。电生理记录结果显示，突触传递功能出现异常。在所分析的所有脑区中，miR-7与miR-671的表达均出现特异性的转录后调控紊乱。即刻早期基因（如作为miR-7直接靶标的Fos）的表达在Cdr1as缺陷型小鼠大脑中显著上调，这为该行为表型提供了潜在的分子关联机制。本研究数据揭示了一种体内功能丧失型环状RNA表型，并表明Cdr1as与微小RNA的相互作用对于维持正常大脑功能具有重要意义。本研究针对四个脑区——小脑、大脑皮层、海马体（含2个基因敲除重复样本）及嗅球——的3个基因敲除组与3个野生型组重复样本开展了微小RNA测序。