MicroRNAs (miRNAs) are endogenous 22 nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
In an investigation inspiring for both its perseverance and its scientific insight, Victor Ambros and colleagues, Rosalind Lee and Rhonda Feinbaum, discovered that lin-4, a gene known to control the timing of C. elegans larval development, does not code for a protein but instead produces a pair of small RNAs (Lee et al., 1993). One RNA is approximately 22 nt in length, and the other is approximately 61 nt; the longer one was predicted to fold into a stem loop proposed to be the precursor of the shorter one. The Ambros and Ruvkun labs then noticed that these lin-4 RNAs had antisense complementarity to multiple sites in the 3′ UTR of the lin-14 gene (Lee et al. 1993 and Wightman et al. 1993). This complementarity fell in a region of the 3′ UTR previously proposed to mediate the repression of lin-14 by the lin-4 gene product (Wightman et al., 1991). The Ruvkun lab went on to demonstrate the importance of these complementary sites for regulation of lin-14 by lin-4, showing also that this regulation substantially reduces the amount of LIN-14 protein without noticeable change in levels of lin-14 mRNA. Together, these discoveries supported a model in which the lin-4 RNAs pair to the lin-14 3′ UTR to specify translational repression of the lin-14 message as part of the regulatory pathway that triggers the transition from cell divisions of the first larval stage to those of the second (Lee et al. 1993 and Wightman et al. 1993).
The shorter lin-4 RNA is now recognized as the founding member of an abundant class of tiny regulatory RNAs called microRNAs or miRNAs (Lagos-Quintana et al. 2001; Lau et al. 2001 and Lee and Ambros 2001). The breadth and importance of miRNA-directed gene regulation are coming into focus as more miRNAs and their regulatory targets and functions are discovered. Recently discovered miRNA functions include control of cell proliferation, cell death, and fat metabolism in flies (Brennecke et al. 2003 and Xu et al. 2003), neuronal patterning in nematodes (Johnston, R.J. and Hobert, O., 2003. A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426, pp. 845–849. View Record in Scopus | Cited By in Scopus (333)Johnston and Hobert, 2003), modulation of hematopoietic lineage differentiation in mammals (Chen et al., 2004), and control of leaf and flower development in plants (Aukerman and Sakai 2003; Chen 2003; Emery et al. 2003 and Palatnik et al. 2003). Computational approaches for finding messages controlled by miRNAs indicate that these examples represent a very small fraction of the total (Rhoades et al. 2002; Enright et al. 2003; Lewis et al. 2003 and Stark et al. 2003).
This review highlights what has been learned about miRNAs in the decade since the report of the lin-4 RNA and its regulation of lin-14. The major topics discussed are miRNA genomics, miRNA biogenesis, miRNA regulatory mechanisms, and the roles of miRNAs in gene regulatory pathways.