MicroRNAs Dynamically Remodel Gastrointestinal Smooth Muscle Cells

Smooth muscle cells (SMCs) express a unique set of microRNAs (miRNAs) which regulate and maintain the differentiation state of SMCs. The goal of this study was to investigate the role of miRNAs during the development of gastrointestinal (GI) SMCs in a transgenic animal model. We generated SMC-specific Dicer null animals that express the reporter, green fluorescence protein, in a SMC-specific manner. SMC-specific knockout of Dicer prevented SMC miRNA biogenesis, causing dramatic changes in phenotype, function, and global gene expression in SMCs: the mutant mice developed severe dilation of the intestinal tract associated with the thinning and destruction of the smooth muscle (SM) layers; contractile motility in the mutant intestine was dramatically decreased; and SM contractile genes and transcriptional regulators were extensively down-regulated in the mutant SMCs. Profiling and bioinformatic analyses showed that SMC phenotype is regulated by a complex network of positive and negative feedback by SMC miRNAs, serum response factor (SRF), and other transcriptional factors. Taken together, our data suggest that SMC miRNAs are required for the development and survival of SMCs in the GI tract.平滑肌细胞（SMCs）表达一套独特的微小RNA（miRNAs），这些微小RNA可调控并维持平滑肌细胞的分化状态。本研究旨在借助转基因动物模型，探究微小RNA在胃肠道（GI）平滑肌细胞发育过程中发挥的作用。我们构建了可通过平滑肌细胞特异性方式表达报告基因绿色荧光蛋白（Green Fluorescence Protein, GFP）的平滑肌细胞特异性Dicer敲除动物。平滑肌细胞特异性敲除Dicer可阻断平滑肌细胞内微小RNA的生物合成，进而引发平滑肌细胞表型、功能及全基因组基因表达的显著改变：突变小鼠出现严重的肠道扩张，并伴随平滑肌（SM）层的变薄与破坏；突变肠道的收缩运动能力显著降低；且突变平滑肌细胞内的平滑肌收缩相关基因与转录调控因子均被广泛下调。表达谱分析与生物信息学分析结果显示，平滑肌细胞表型受平滑肌细胞微小RNA、血清反应因子（SRF）及其他转录因子构成的复杂正负反馈网络调控。综上，本研究数据表明，胃肠道平滑肌细胞的发育与存活离不开平滑肌细胞微小RNA。