Liu Ning, Bezprozvannaya Svetlana, Williams Andrew H, Qi Xiaoxia, Richardson James A, Bassel-Duby Rhonda, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Genes Dev. 2008 Dec 1;22(23):3242-54. doi: 10.1101/gad.1738708. Epub 2008 Nov 17.
MicroRNAs (miRNAs) modulate gene expression by inhibiting mRNA translation and promoting mRNA degradation, but little is known of their potential roles in organ formation or function. miR-133a-1 and miR-133a-2 are identical, muscle-specific miRNAs that are regulated during muscle development by the SRF transcription factor. We show that mice lacking either miR-133a-1 or miR-133a-2 are normal, whereas deletion of both miRNAs causes lethal ventricular-septal defects in approximately half of double-mutant embryos or neonates; miR-133a double-mutant mice that survive to adulthood succumb to dilated cardiomyopathy and heart failure. The absence of miR-133a expression results in ectopic expression of smooth muscle genes in the heart and aberrant cardiomyocyte proliferation. These abnormalities can be attributed, at least in part, to elevated expression of SRF and cyclin D2, which are targets for repression by miR-133a. These findings reveal essential and redundant roles for miR-133a-1 and miR-133a-2 in orchestrating cardiac development, gene expression, and function and point to these miRNAs as critical components of an SRF-dependent myogenic transcriptional circuit.
微小RNA（miRNA）通过抑制mRNA翻译和促进mRNA降解来调节基因表达，但它们在器官形成或功能中的潜在作用却鲜为人知。miR-133a-1和miR-133a-2是相同的、肌肉特异性的miRNA，在肌肉发育过程中受SRF转录因子调控。我们发现，缺失miR-133a-1或miR-133a-2的小鼠是正常的，而同时缺失这两种miRNA会在大约一半的双突变胚胎或新生儿中导致致命的室间隔缺损；存活至成年的miR-133a双突变小鼠会死于扩张型心肌病和心力衰竭。miR-133a表达缺失导致心脏中平滑肌基因的异位表达以及心肌细胞增殖异常。这些异常至少部分可归因于SRF和细胞周期蛋白D2的表达升高，它们是miR-133a的抑制靶点。这些发现揭示了miR-133a-1和miR-133a-2在协调心脏发育、基因表达和功能方面的重要且冗余的作用，并指出这些miRNA是SRF依赖性肌源性转录回路的关键组成部分。
