AGO2 slicing of a domesticated retrotransposon is necessary for normal vasculature development

Argonaute (AGO) mediated slicing of RNA-also known as RNAi-is a highly conserved phenomenon that is evolutionarily linked to the repression of transposons and other repeats. Although RNAi is no longer a major mechanism of repeat control in mammals, AGO2 has retained cleavage competence and is able to efficiently cut RNAs with extensive complementarity to a bound guide. The regulatory roles this activity plays in mammals however remains poorly understood. Here we show that mice carrying two catalytically inactive Ago2 alleles have extensive developmental abnormalities including systemic vascular defects that are characterized by enlarged and leaky vessels and stem from endothelial cell dysfunction. Endothelial cell defects are caused by failure to repress Rtl1 , a paternally-imprinted domesticated retrotransposon, whose cleavage in wild-type animals is triggered by miRNAs of the maternally-imprinted miR-433∼127 cluster. Our data pinpoint an essential mRNA cleavage target of AGO2 and suggest that the repurposing of a TE-Argonaute regulatory interaction contributes to the retention of AGO catalytic competence in mammals.