11 Regulation of mRNA Molecules by MicroRNAs

Abstract

Twenty-two years before microRNAs (miRNAs) would become Science’s “the 2001 molecule of the year,” the first miRNA, lin-4, was discovered in Caenorhabditis elegans. Since then, these small noncoding RNA molecules, approximately 22 nucleotides in length, have been detected in many eukaryotic organisms, and it is estimated that they control approximately one-fourth of all cellular mRNAs at the posttranscriptional level. This chapter focuses primarily on animal miRNAs and their roles in posttranscriptional control of gene expression.

HISTORICAL BACKGROUND ON ANIMAL miRNAs
lin-4 was identified as a loss-of-function mutation that gave rise to re-iterations in cell lineages, retarded development, and abnormal morphology in C. elegans (Horvitz and Sulston 1980; Chalfie et al. 1981). Additional genetic screens identified semidominant gain-of-function mutations in the lin-14 gene that, like the lin-4 mutation, led to cell lineage reiteration and retarded development (Ambros and Horvitz 1984Ambros and Horvitz 1987). On the basis of the similar phenotypes of the lin-4 loss-of-function and lin-14 gain-of-function mutants, it was postulated that the two genes interact genetically (Ambros 1989). Indeed, epistasis experiments revealed that the lin-4 mutant phenotype was dependent on lin-14, suggesting that the role of the lin-4 gene product is to act as a negative regulator of lin-14 (Ambros 1989).

The mechanism by which lin-4 negatively regulates lin-14 was unknown until 1991, when it was demonstrated that the lin-4 gene product down-regulated lin-14 protein levels by interacting with the lin-14 3′ untranslated region (3′UTR) (Arasu et al. 1991; Wightman et al. 1991). Subsequently, the lin-4 gene product was discovered to be...