Max-Planck-Institut für Herz- und Lungenforschung, Department of Cardiac Development and Remodelling, Bad Nauheim, Germany.
PLoS Genet. 2013;9(9):e1003793. doi: 10.1371/journal.pgen.1003793. Epub 2013 Sep 19.
miRNAs are small RNAs directing many developmental processes by posttranscriptional regulation of protein-coding genes. We uncovered a new role for miR-1-1/133a-2 and miR-1-2/133a-1 clusters in the specification of embryonic cardiomyocytes allowing transition from an immature state characterized by expression of smooth muscle (SM) genes to a more mature fetal phenotype. Concomitant knockout of miR-1-1/133a-2 and miR-1-2/133a-1 released suppression of the transcriptional co-activator myocardin, a major regulator of SM gene expression, but not of its binding partner SRF. Overexpression of myocardin in the embryonic heart essentially recapitulated the miR-1/133a mutant phenotype at the molecular level, arresting embryonic cardiomyocytes in an immature state. Interestingly, the majority of postulated miR-1/133a targets was not altered in double mutant mice, indicating that the ability of miR-1/133a to suppress target molecules strongly depends on the cellular context. Finally, we show that myocardin positively regulates expression of miR-1/133a, thus constituting a negative feedback loop that is essential for early cardiac development.
miRNAs 是通过对蛋白质编码基因的转录后调控来指导许多发育过程的小分子 RNA。我们发现了 miR-1-1/133a-2 和 miR-1-2/133a-1 簇在胚胎心肌细胞特化中的新作用，使细胞从以平滑肌 (SM) 基因表达为特征的不成熟状态过渡到更成熟的胎儿表型。miR-1-1/133a-2 和 miR-1-2/133a-1 的同时敲除释放了转录共激活因子 myocardin 的抑制作用，myocardin 是 SM 基因表达的主要调节因子，但不是其结合伴侣 SRF。心肌球蛋白在胚胎心脏中的过表达在分子水平上基本上重现了 miR-1/133a 突变体的表型，使胚胎心肌细胞停留在不成熟状态。有趣的是，在双突变小鼠中，大多数假定的 miR-1/133a 靶标没有改变，这表明 miR-1/133a 抑制靶分子的能力强烈依赖于细胞环境。最后，我们表明 myocardin 正向调节 miR-1/133a 的表达，从而构成了一个负反馈回路，这对早期心脏发育至关重要。
