Survival Interference in the Fly
Published online at Lab Times.
The Nobel Prize discovery of RNA interference set the stage for rapid and robust gene function studies in vitro. The technique has been extensively used for genetic screens in the worm but rarely for ageing studies in the fruit fly. British researchers uncover the reason behind.
RNA interference (RNAi), a multi-step cellular mechanism first described in the worm Caenorhabditis elegans in the 90’s, is now routinely used to identify gene function as it can generate acute loss-of-functions by destroying protein-coding RNA. The approach has waylaid the identification of, for instance, various ‘ageing’-related genes in the nematode. Nazif Alic, a postdoc at the Institute of Healthy Ageing, University College London (UCL), however, was intrigued by the lack of congruent reports in Drosophila. His investigations, published in a recent issue of PLoS ONE, shed light on the deleterious effects of RNAi on the fruit fly’s lifespan.
While several RNAi constructs, by silencing target genes, have been shown to improve the lifespan in C. elegans, analogous observations have rarely been noted in the fly. “It is not that there are no ‘ageing’ genes in Drosophila. Indeed, mutants and dominant-negatives of certain genes stimulate lifespan in the fly but what concerned me was why RNAi constructs cannot recapitulate such protective effects,” recalls Nazif. That’s when he hypothesized that RNAi by itself could be toxic to the fly.
In their paper, Nazif and co-workers demonstrated that genetic manipulations using non-sequence-specific RNAi, targeting proteins not expressed in the fly, reduce lifespan. Further, overexpression of components of the RNAi machinery has similar detrimental effects on lifespan confirming the toxicity of triggering the pathway. A possible explanation they propose is an RNAi-evoked altered response of adult fly health to lifespan-shortening effects of certain foods.
But why are the toxic effects of RNAi not apparent in C. elegans? Though he does not really know, Nazif postulates that introducing RNAi in Drosophila may be diluting some component that it shares with the micro-RNA processing machinery.
Nazif, who is on the verge of establishing his own research group at UCL, currently works in the lab of Linda Partridge. A broader aim of the lab is to achieve extended lifespan in flies by interfering with insulin signalling. Their report on the toxicity of RNAi exercises a word of caution on the use of this attractive tool in genetic manipulations and calls for the use of appropriate controls for maximizing the accuracy of such studies.
Photo: Fruit fly by Max Westby via Creative Commons License