Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing

Significance The germline, which produces sperm or oocyte, is separated from other cells that generate the rest of the body, the soma, during early development in most animals. Somatic cells experience and respond to the environment in each generation, and it is unknown whether they can transmit information to the germline for inheritance into subsequent generations. We found that neurons of the worm Caenorhabditis elegans can transmit double-stranded RNA to the germline to initiate transgenerational silencing of a gene of matching sequence. To our knowledge, these results demonstrate for the first time that a somatic tissue of an animal can have transgenerational effects on a gene through the transport of double-stranded RNA to the germline. An animal that can transfer gene-regulatory information from somatic cells to germ cells may be able to communicate changes in the soma from one generation to the next. In the worm Caenorhabditis elegans , expression of double-stranded RNA (dsRNA) in neurons can result in the export of dsRNA-derived mobile RNAs to other distant cells. Here, we show that neuronal mobile RNAs can cause transgenerational silencing of a gene of matching sequence in germ cells. Consistent with neuronal mobile RNAs being forms of dsRNA, silencing of target genes that are expressed either in somatic cells or in the germline requires the dsRNA-selective importer SID-1. In contrast to silencing in somatic cells, which requires dsRNA expression in each generation, silencing in the germline is heritable after a single generation of exposure to neuronal mobile RNAs. Although initiation of inherited silencing within the germline requires SID-1, a primary Argonaute RDE-1, a secondary Argonaute HRDE-1, and an RNase D homolog MUT-7, maintenance of inherited silencing is independent of SID-1 and RDE-1, but requires HRDE-1 and MUT-7. Inherited silencing can persist for >25 generations in the absence of the ancestral source of neuronal dsRNA. Therefore, our results suggest that sequence-specific regulatory information in the form of dsRNA can be transferred from neurons to the germline to cause transgenerational silencing.