Movement of regulatory RNA between animal cells

Abstract

Summary Recent studies suggest that RNA can move from one cell to another and regulate genes through specific base-pairing. Mechanisms that modify or select RNA for secretion from a cell are unclear. Secreted RNA can be stable enough to be detected in the extracellular environment and can enter the cytosol of distant cells to regulate genes. Mechanisms that import RNA into the cytosol of an animal cell can enable uptake of RNA from many sources including other organisms. This role of RNA is akin to that of steroid hormones, which cross cell membranes to regulate genes. The potential diagnostic use of RNA in human extracellular fluids has ignited interest in understanding mechanisms that enable the movement of RNA between animal cells. Genetic model systems will be essential to gain more confidence in proposed mechanisms of RNA transport and to connect an extracellular RNA with a specific biological function. Studies in the worm C. elegans and in other animals have begun to reveal parts of this novel mechanism of cell-to-cell communication. Here, I summarize the current state of this nascent field, highlight the many unknowns, and suggest future directions.

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

“…Similar direct delivery to progeny could underlie parental RNAi in insects (reviewed in ref. 14), when dsRNA is delivered into the hemocoel (e.g., ref. 43) or through ingestion (e.g., ref.…”

Artificial and natural RNA interactions between bacteria andC. elegans

“…25 In the intervening year, working to understand how dsRNA injected into one tissue could lead to silencing in other tissues, Winston and Hunter reported the results of the first genetic screens for this so-called systemic RNAi, uncovering systemic RNAi deficient (Sid) genes, including sid-1, 51 which encodes a dsRNA specific transmembrane channel. 7 A second Sid protein, SID-2, which is a single pass trans-membrane protein, was found to be essential for environmental RNAi (See detailed review 24 ). The systemic RNAi genes are distinct from the genes involved in the canonical RNAi pathway described above and are not required for RNAi itself.…”

Uptake and impact of natural diet-derived small RNA in invertebrates: Implications for ecology and agriculture

“…80 The majority of our information about the mechanism for dietary uptake of sRNA comes from nematodes (reviewed in 81 ). C. elegans possess a pathway for sRNA uptake by cells that was identified in a screen for systemic RNAi defective (SID) mutants.…”

“…In addition, miRNAs have been found in C. elegans interstitial fluid 99 and D. melanogaster hemolymph 100 suggesting extracellular transport. Furthermore, the existence of endocytotic mechanisms for systemic RNAi spread in both organisms, 81,101,102 suggests that extracellular sRNA exists in invertebrates. However, there are no data on the form extracellular sRNA takes in invertebrate species.…”