MicroRNAs and cell differentiation in mammalian development

Abstract

MicroRNAs (miRNAs) are a group of recently discovered small RNAs produced by the cell using a unique process, involving RNA polymerase II, Microprocessor protein complex, and the RNAase III/Dicer endonuclease complex, and subsequently sequestered in an miRNA ribonucleoprotein complex. The biological functions of miRNAs depend on their ability to silence gene expression, primarily via degradation of the target mRNA and/or translational suppression, mediated by the RNA-induced silencing complex (RISC). First discovered in Caenorhabditis elegans (lin-4), miRNAs have now been identified in a wide array of organisms, including plants, zebrafish, Drosophila, and mammals. The expression of miRNAs in multicellular organisms exhibits spatiotemporal, and tissue- and cell-specificity, suggesting their involvement in tissue morphogenesis and cell differentiation. More than 200 miRNAs have been identified or predicted in mammalian cells. Recent studies have demonstrated the importance of miRNAs in embryonic stem cell differentiation, limb development, adipogenesis, myogenesis, angiogenesis and hematopoiesis, neurogenesis, and epithelial morphogenesis. Overexpression (gain-of-function) and inactivation (loss-of-function) are currently the primary approaches to studying miRNA functions. Another family of small RNAs related to miRNAs is the small interfering RNAs (siRNAs), generated by Dicer from long double-stranded RNAs (dsRNAs), and produced from an induced transgene, a viral intruder, or a rogue genetic element. siRNAs silence genes via either mRNA degradation, using the RISC, or DNA methylation. siRNAs are actively being applied in basic, functional genetic studies, particularly in the generation of gene knockdown animals, as well as in gene knockdown studies of cultured cells. These studies have provided invaluable information on the specific function(s) of individual genes. siRNA technology also presents exciting potential as a therapeutic approach in disease prevention and treatment, as suggested by a recent study targeting apolipoprotein B (ApoB) in primates. Further elucidation of how miRNAs and other small RNAs interact with known and yet-to-be identified gene regulatory pathways in the cell should provide us with a more in-depth understanding of the mechanisms regulating cellular function and differentiation, and facilitate the application of small RNA technology in disease control and treatment.