MicroRNA Mechanisms of Action: What have We Learned from Mice?

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MicroRNAs (miRNAs) are endogenously encoded single-stranded RNAs of about 22 nucleotides (nts) in length that play essential roles in a large variety of physiological processes in animals and plants (Ambros, 2004; Bushati and Cohen, 2007). Mature miRNAs are integrated into the RNA-induced silencing complex (RISC), whose core component is one of the Argonaute family proteins. MiRNAs then direct RISCs to target mRNAs, which are recognized through partial sequence complementarity. Bioinformatic prediction and experimental target gene identification have shown that a miRNA binds mRNAs of hundreds of protein coding genes, which often span a broad spectrum of functional categories (Bartel, 2009; Chi et al., 2009; Hafner et al., 2010). The functional consequence of miRNA-target mRNA interaction and the mechanism of miRNA action have been under intensive investigation and remain a matter of hot debate. It was initially thought that miRNAs repress the protein output of a small number of target genes without significantly affecting their mRNA levels in animals (Lee et al., 1993; Wightman et al., 1993). Subsequent genetic studies in C. elegans and zebrafish showed that miRNAs promote the degradation of their target mRNAs (Bagga et al., 2005; Giraldez et al., 2006). Later, a series of genome-wide studies of in vitro cultured mammalian cell lines transiently transfected with chemically synthesized miRNA mimics led to the conclusion that the predominant functional consequence of miRNA action is target mRNA degradation (Guo et al., 2010). A follow-up study employing temporal dissection of zebrafish development seems to reconcile these two opposite observations by revealing that translational repression precedes target mRNA decay, and suggesting that the immediate outcome of miRNA-target mRNA interaction is translation inhibition but mRNA degradation can follow (Bazzini et al., 2012). Similarly, re-analysis of the previous datasets from cultured cell lines transiently transfected with synthetic miRNA mimics also found that translation repression precedes mRNA degradation (Larsson and Nadon, 2013).