January 29th, 2009
Antony M. Jose and Craig P. Hunter
Distant cells in our body talk to each other to co-ordinate what they do. Typically, one cell sends a signal that is recognized by specialized receptors on the surface of another distant cell. These signal-bound receptors then transduce the signal and instruct the cell to generate an appropriate response. Our recent experiments, published in Proceedings of the National Academy of Sciences (PNAS), revealed a paradigm of highly specific communication between cells that can occur without such signal transduction. Using the simple worm C. elegans, we found that an animal cell can directly control the activity of specific genes in other cells by transporting regulatory RNAs of matching sequence into these distant cells.
When cells of many organisms, including humans, encounter double-stranded RNA (dsRNA), the gene with matching sequence is silenced. Such RNA interference (RNAi) is being exploited as an effective therapeutic approach to silence “non-druggable” disease genes, which lack effective small-molecule drugs. The dsRNA is taken into cells through a dsRNA channel SID-1 in C. elegans and through a similar SID-1-like dsRNA channel into human cells. If cells use such conserved machinery to import dsRNA, do other cells make and export dsRNA? Intercellular bridges called plasmadesmata mediate transport of dsRNA and other macromolecules including proteins between cells in plants. But, although animals–including humans–express numerous dsRNAs from their genome, no obvious route for the export of dsRNA is known in animals. Therefore, whether expressed dsRNAs are transported between cells in animals is unclear.
Our study shows that many cell-types in C. elegans can make and export dsRNAs. C. elegans cells can detect multi-copy foreign DNA and use dsRNA derived from it to neutralize its effects through RNAi. We found that these cells also export mobile silencing signals that instruct and/or help other cells to mount an effective response against the same foreign DNA. The mobile silencing signal is likely to be a form of dsRNA, since the dsRNA channel SID-1 is required for the import of the signal into cells. We detected widespread ability to transport such dsRNA signals among tissues: from neurons to gut, skin, and muscles; from muscles to gut and skin; and from throat to gut and muscles.
Since SID-1 is required for the import of dsRNA into cells, it was a natural suspect for mediating their export. To our surprise, we found that even tissues that lack SID-1 could export dsRNA, suggesting that dsRNA export can occur through an as yet unidentified mechanism. Similarly, when worms eat bacteria that make dsRNA, the dietary dsRNA is transported across the gut and into the animal even when the gut lacks SID-1.
Several interesting questions are raised by our study. How do disparate tissues such as gut, muscles, and neurons all export RNA? Why? Is this a general way for the entire organism to respond to instructions from individual organs and tissues? Given that human SID-1 imports dsRNA into cells, do human cells also export dsRNAs? Since the use of dsRNA for RNAi is being vigorously pursued as a therapeutic approach for several diseases, immediate evaluation of these RNA transport pathways in mammals is warranted to enable safe and specific delivery of dsRNA for RNAi therapy.
Read more in PNAS