Abstract
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.
Highlights
Dicer is a key endonuclease in the RNA interference machinery that cleaves precursor microRNAs into mature miRNAs during miRNA biogenesis [1,2]
Generation of smDicer mutant mice Smooth muscle cells (SMCs)-specific Dicer null smDicer2/2;Cre-GFP/+ mice were generated by cross-breeding a smMHC/Cre/Enhanced green fluorescent protein (eGFP) male mouse [31] and a Dicerlox/lox female homozygote mouse (The Jackson Laboratory) according to a procedure approved by the Institutional Animal Care and Use Committee at the University of Nevada, Reno
The smDicer KO mice implicated in the regulation of SMC phenotype by the serum response factor (SRF)-dependent, SMC-phenotypic miRNAs
Summary
Dicer is a key endonuclease in the RNA interference machinery that cleaves precursor microRNAs (miRNAs) into mature miRNAs during miRNA biogenesis [1,2]. Tissue or cell-specific knockout studies of Dicer have been performed to uncover the functions of miRNAs during the development of cells including embryonic stem cells [3], female germline cells [4], testis Sertoli cells [5], pancreatic islet cells [6], lung epithelial cells [7], and skeletal chondrocytes [8]. These studies show that miRNAs are essential in cell proliferation and/or differentiation during development. SRF binds to the CArG box, which transcriptionally activates or represses SM genes, depending on its associated cofactors
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