Discussion

Schistosome egg production is the primary driver of morbidity due to infection, thus it is paramount that we establish a better understanding of the molecular mechanisms that control sexual development. Interestingly, female schistosomes require close physical contact with male worms to become sexually mature and to maintain the ability to produce eggs. Although this phenomenon was described nearly 100 years ago, the molecular mechanisms are unresolved. Here, we show that the transcription factor GLI1 is essential in male schistosomes to induce the expression of a non-ribosomal peptide synthetase (SmNRPS) expressed in ciliated neurons along the males ventral surface where the male worms interface with the female. Loss of either GLI1 or SmNRPS renders males incapable of inducing female sexual development. Using a combination of in vitro biochemistry and metabolomics, we find that SmNRPS produces a dipeptide exclusively in paired male worms and that this dipeptide is capable of stimulating virgin female sexual development in the absence of the males. Not only do these studies discover a novel flatworm pheromone and signaling molecule, they provide a molecular mechanism for male-induced female sexual development in schistosomes.