Single-cell analysis of Schistosoma mansoni identifies a conserved genetic program controlling germline stem cell...

Schistosomes are parasitic flatworms causing one of the most prevalent infectious diseases from which millions of people are currently suffering. These parasites have high fecundity and their eggs are both the transmissible agents and the cause of the infection-associated pathology. Given its biomedical significance, the schistosome germline has been a research focus for more than a century. Nonetheless, molecular mechanisms that regulate its development are only now being understood. In particular, it is unknown what balances the fate of germline stem cells (GSCs) in producing daughter stem cells through mitotic divisions versus gametes through meiosis. Here, we perform single-cell RNA sequencing on juvenile schistosomes and capture GSCs during de novo gonadal development. We identify a genetic program that controls the proliferation and differentiation of GSCs. This program centers around onecut, a homeobox transcription factor, and boule, an mRNA binding protein. Their expressions are mutually dependent in the schistosome male germline, and knocking down either of them causes over-proliferation of GSCs and blocks germ cell differentiation. We further show that this germline-specific regulatory program is conserved in the planarian, schistosome's free-living evolutionary cousin, but the function of onecut has changed during evolution to support GSC maintenance.