Concepts and functions of small RNA pathways in C. elegans

A diversity of gene regulatory mechanisms drives the changes in gene expression required for animal development. Here, we discuss the developmental roles of a class of gene regulatory factors composed of a core protein subunit of the Argonaute family and a 21–26-nucleotide RNA cofactor. These represent ancient regulatory complexes, originally evolved to repress genomic parasites such as transposons, viruses and retroviruses. However, over the course of evolution, small RNA-guided pathways have expanded and diversified, and they play multiple roles across all eukaryotes. Pertinent to this review, Argonaute and small RNA-mediated regulation has acquired numerous functions that affect all aspects of animal life. The regulatory function is provided by the Argonaute protein and its interactors, while the small RNA provides target specificity, guiding the Argonaute to a complementary RNA. C. elegans has 19 different, functional Argonautes, defining distinct yet interconnected pathways. Each Argonaute binds a relatively well-defined class of small RNA with distinct molecular properties. A broad classification of animal small RNA pathways distinguishes between two groups: (i) the microRNA pathway is involved in repressing relatively specific endogenous genes and (ii) the other small RNA pathways, which effectively act as a genomic immune system to primarily repress expression of foreign or “non-self” RNA while maintaining correct endogenous gene expression. microRNAs play prominent direct roles in all developmental stages, adult physiology and lifespan. The other small RNA pathways act primarily in the germline, but their impact extends far beyond, into embryogenesis and adult physiology, and even to subsequent generations. Here, we review the mechanisms and developmental functions of the diverse small RNA pathways of C. elegans.