Ubiquitous expression of long dsRNA in mice causes mainly RNAi effects in the oocyte

Double-stranded RNA (dsRNA) can enter different pathways in mammalian cells, such as the sequence-specific RNA interference (RNAi) pathway, the sequence-independent interferon response, and RNA editing by adenosine deaminases. To study routing of long dsRNA into different pathways in different tissues, we generated transgenic mice carrying an inverted repeat transcribed by a strong, ubiquitously active polII promoter. Here, we provide the first report of effects caused by ubiquitous long dsRNA expression in the adult mouse. Long dsRNA is poorly processed into siRNAs in somatic cells but readily induces the RNAi effects in the oocyte, suggesting that somatic cells are missing a component of RNAi that facilitates siRNA biogenesis. Expression of dsRNA is not sufficient to activate the interferon pathway and has a minimal effect on the transcriptome in somatic cells. The interferon response in somatic cells could be induced with high doses of dsRNA expression, suggesting that somatic cells can tolerate endogenous dsRNA expression to a large extent. Our data demonstrate that the association between long dsRNA and the interferon pathway in somatic cells cannot be generalized and that cells recognize other features of dsRNA molecules, which increase or reduce the likelihood activation of a particular dsRNA-induced pathway. Overall design: Brain or kidney tissue (transgenic mice), or HEK293 or HeLa cell lines (human), expressing long dsRNA within the 3'-UTR of the EGFP reporter gene.