Abstract
In adult testis, the cell mobility is essential for spermatogonia differentiation and is suspected to regulate spermatogonial stem cell fate. Netrin-1 controls cell migration and/or survival according to the cellular context. Its involvement in some self-renewing lineages raises the possibility that Netrin-1 could have a role in spermatogenesis. We show that in addition to Sertoli cells, a fraction of murine undifferentiated spermatogonia express the Netrin-1 receptor UNC5c and that UNC5c contributes to spermatogonia differentiation. Receptor loss in Unc5crcm males leads to the concomitant accumulation of transit-amplifying progenitors and short syncytia of spermatogonia. Without altering cell death rates, the consequences of Unc5c loss worsen with age: the increase in quiescent undifferentiated progenitors associated with a higher spermatogonial stem cell enriched subset leads to the spermatocyte I decline. We demonstrate in vitro that Netrin-1 promotes a guidance effect as it repulses both undifferentiated and differentiating spermatogonia. Finally, we propose that UNC5c triggers undifferentiated spermatogonia adhesion/ migration and that the repulsive activity of Netrin-1 receptors could regulate spermatogonia differentiation, and maintain germ cell homeostasis.