RNAi may target the double-stranded RNA (dsRNA) forms of invading viruses or mobile transposons, but in the laboratory dsRNA is used to trigger the destruction of mRNAs with the same sequence. In worms and, in a similar process, in plants, the destruction spreads systemically.
“This systemic effect greatly simplifies the use of RNAi as a genetic tool,” says Hunter, as worms can even be treated by soaking them in a solution of dsRNA. “But nobody has addressed it experimentally to discover how it works.” Hunter set out to find mutants that could still do localized RNAi, in cells expressing both a dsRNA and a corresponding target gene, but could no longer spread that RNAi signal to other cells expressing only the target gene.One of the three genes that he found, called sid-1, encodes a protein with 11 predicted transmembrane domains. There are homologues in mice and humans and “the strongest homology is in the transmembrane regions, so we'd like to think it's acting as a channel.” The alternative explanation—that SID-1 is a receptor mediating endocytosis of an RNAi signal—would be more likely if the homology was concentrated in the extracellular domain.
Hunter hopes to test the channel theory in worm primary tissue culture cells. And with SID-1 in hand, he can test whether systemic RNAi operates in mice and other mammals, and what it might be doing there. ▪