Zhao Yong, Ransom Joshua F, Li Ankang, Vedantham Vasanth, von Drehle Morgan, Muth Alecia N, Tsuchihashi Takatoshi, McManus Michael T, Schwartz Robert J, Srivastava Deepak
Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Cell. 2007 Apr 20;129(2):303-17. doi: 10.1016/j.cell.2007.03.030. Epub 2007 Mar 29.
MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 "seed matches" and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.
微小RNA（miRNA）是生物体用于调控信使核糖核酸转录本所产生蛋白质表达的基因组编码小RNA。通过靶向缺失对哺乳动物体内特定miRNA的需求仍不清楚，且对信使核糖核酸靶标的可靠预测仍存在问题。在此，我们表明小鼠心脏中的miRNA生物合成对于心脏发生至关重要。此外，肌肉特异性miRNA miR-1-2的靶向缺失揭示了其在心脏中的众多功能，包括对心脏形态发生、电传导和细胞周期控制的调控。对miR-1-2缺失后上调的信使核糖核酸中miR-1互补序列的分析显示，miR-1“种子匹配”富集，且潜在miR-1结合位点有强烈倾向位于物理可及区域。这些发现表明，miRNA剂量的细微改变在哺乳动物中可能产生深远影响，并证明了哺乳动物功能丧失模型在揭示生理性miRNA靶标方面的实用性。
