Glial cells gate small RNA transport from germline to brain during transgenerational epigenetic inheritance of behavior

How circulating RNAs reach their target tissue is not well understood. In C. elegans, small RNA signals that convey exposure to pathogenic Pseudomonas travel from the intestine to germline to neurons, allowing both learned pathogen avoidance and the transgenerational inheritance of this information for four generations, but how this Cer1 retrotransposon-bound RNA signal reaches the nervous system was previously unknown. We found that the RNA transporter SID-1, long thought to act in the intestine or germline, instead functions in a single cell type, the amphid sheath glia, where it is necessary and sufficient for learned avoidance. SID-1 mediates uptake of germline-derived RNA, followed by transcytosis to a neighboring sensory neuron, where the P11 target gene maco-1 is silenced. This glial "filter", which uses highly conserved molecular components to transcytose RNAs to neurons, reveals a general mechanism for gating small RNA access to the nervous system, paralleling the mammalian blood-brain barrier.