Double stranded RNA sensing is silenced during early embryonic development

The type I interferon response is inactive during early mammalian development and becomes functional only after gastrulation. As a result, the totipotent and pluripotent embryonic stages remain susceptible to pathogens, including viruses. Here, we demonstrate that pluripotent mouse embryonic stem cells suppress the RIG-I-like receptor sensing pathway by silencing the expression of the double stranded RNA sensor MDA5. This silencing is necessary to avoid the recognition of double stranded RNAs of endogenous origin, which accumulate in mouse embryonic stem cells. Reintroducing MDA5 results in recognition of these endogenous double stranded RNAs and triggers the activation of the IFN response through IRF3. The production of interferon alters the differentiation ability of mouse embryonic stem cells, and affects the pluripotency gene expression programme, as shown by epigenetic, transcriptomic and proteomic analyses. Further, we show that zebrafish also repress MDA5 expression in early development and lack early-stage interferon activation, and that inducing double-stranded RNA-mediated signalling at this stage results in developmental defects. Altogether, we conclude that silencing the RIG-I-like receptor pathway during early development is important in preventing aberrant immune recognition of endogenous double stranded RNAs, safeguarding normal development.