small RNA Pfs1 mediates transgenerational epigenetic inheritance of pathogen avoidance in through the Ephrin receptor VAB-1.

are exposed to a variety of pathogenic and non-pathogenic bacteria species in their natural environment. Correspondingly, has evolved an ability to discern between nutritive and infectious bacterial food sources. Here we show that can learn to avoid the pathogenic bacteria (PF15), and that this learned avoidance behavior is passed on to progeny for four generations, as we previously demonstrated for (PA14) and , using similar mechanisms, including the involvement of both the TGF-β ligand DAF-7 and retrotransposon-encoded virus-like particles. PF15 small RNAs are both necessary and sufficient to induce this transgenerational avoidance behavior. Unlike PA14 or , PF15 does not use P11, Pv1, or a small RNA with homology for this avoidance; instead, an unrelated PF15 small RNA, Pfs1, that targets the Ephrin receptor gene is necessary and sufficient for learned avoidance, suggesting the evolution of yet another bacterial sRNA/ gene target pair involved in transgenerational inheritance of pathogen avoidance. As VAB-2 Ephrin receptor ligand and MACO-1 knockdown also induce PF15 avoidance, we have begun to understand the genetic pathway involved in small RNA targeted pathogenic avoidance. Moreover, these data show that axon guidance pathway genes (VAB-1 and VAB-2) have previously unknown adult roles in regulating neuronal function. may have evolved multiple bacterial specificity-encoded small RNA-dependent mechanisms to avoid different pathogenic bacteria species, thereby providing progeny with a survival advantage in a dynamic environment.