Recent Molecular Genetic Explorations of Caenorhabditis elegans MicroRNAs

Abstract

MicroRNAs are small, noncoding RNAs that regulate gene expression at the post-transcriptional level in essentially all aspects of Caenorhabditis elegans biology. More than 140 genes that encode microRNAs in C. elegans regulate development, behavior, metabolism, and responses to physiological and environmental changes. Genetic analysis of C. elegans microRNA genes continues to enhance our fundamental understanding of how microRNAs are integrated into broader gene regulatory networks to control diverse biological processes, including growth, cell division, cell fate determination, behavior, longevity, and stress responses. As many of these microRNA sequences and the related processing machinery are conserved over nearly a billion years of animal phylogeny, the assignment of their functions via worm genetics may inform the functions of their orthologs in other animals, including humans. In vivo investigations are especially important for microRNAs because in silico extrapolation of their functions using mRNA target prediction programs can easily assign microRNAs to incorrect genetic pathways. At this mezzanine level of microRNA bioinformatic sophistication, genetic analysis continues to be the gold standard for pathway assignments.

Keywords: Argonaute; Caenorhabditis elegans; WormBook; miRISC; microRNA; mutant phenotypes.

Figure 1

MicroRNA metabolism and function in C. elegans. Current understanding of major factors involved with various steps in the transcription and processing of microRNA primary transcripts (pri-miRNA) in the nucleus (left), export of the hairpin RNA microRNA precursor (pre-miRNA) through the nuclear pore to the cytoplasm (top), processing of the pre-miRNA by Dicer/DCR-1, and loading of the mature miRNA into a core microRNA-Induced Silencing Complex (miRISC) Argonaute protein (ALG-1). Additional factors assemble with miRISC, including the general miRISC effector protein AIN-1/2. The miRISC complex binds to target mRNAs via complementary sites in their 3′-UTRs and represses protein production from the target by various mechanisms, as discussed in the text. MicroRNAs eventually undergo downregulation through processes involving 3′ terminal uridyl modifications and degradation by the cellular RNA turnover machinery (figure courtesy of Gloria Ha). Pol II, RNA polymerase II: TUTase, terminal uridyl transferase.