Cardiac Dissonance Without Conductors

Abstract

Dicer was initially identified as the protein responsible for processing double-stranded RNA into small interference RNAs.1 Later, it was shown that on interaction with cofactors,2 Dicer also produces other kinds of small RNAs, ie, microRNAs (miRNAs).3 MiRNAs are endogenous small ribonucleotides that act as negative regulators of target messenger RNAs. It has been estimated that the human genome encodes up to 1000 miRNAs that modulate 30% to 50% of all genes, which demonstrates the importance of these small regulators as fundamental orchestrators of the genome. Article p 1567 Primary transcripts (pri-miRNA) are processed in the nucleus into hairpin RNAs by the RNase III–type enzyme Drosha4 and the double-stranded RNA binding protein DGCR85 to form pre-miRNAs. On nuclear export, pre-miRNAs are processed by the ribonuclease Dicer into 19- to 25-nucleotide miRNA duplexes, of which 1 strand is implemented into the RNA-induced silencing complex, which then binds to target mRNAs with subsequent mRNA degradation or translational inhibition.6 Recent data obtained by performance of parallel transcriptome and proteomic analysis in cells transfected with different miRNAs propose that in mammals, miRNAs exert stronger effects on protein expression than on mRNA levels.7 The biological importance of Dicer-mediated maturation of miRNAs has been shown for various cell types, including embryonic stem cells8 and germline cells,9 as well as for more specialized cell types, such as pancreatic islet cells,10 immune cells,11 neural cells,12 or endothelial cells.13 A first role for Dicer in cardiac development was described previously. To assess the global requirement for miRNAs in the mouse heart early during development, Zhao and colleagues14 deleted a floxed Dicer allele using Cre recombinase under control of the endogenous Nkx2.5 regulatory region, which directs expression in cardiac progenitor cells by embryonic day (E) 8.5. This …