TGFß/Activin signaling is a switch between homeostasis and stem cell regeneration in the Drosophila testis

Abstract

The niche provides a distinct microenvironment for stem cells and secretes short range self-renewal cues that promote `stemness` in the resident population. However, whether stem cells also secrete signals that maintain the niche remains an intriguing question. The Drosophila testis provides an ideal system to address this important issue. In this tissue, twelve quiescent niche cells support two mitotic stem cell pools, germline stem cells (GSCs) that ultimately produce sperm and somatic cyst stem cells (CySCs) that support GSCs and produce somatic support cells. Prior work has shown that genetic ablation of all CySCs in the Drosophila testis causes niche cells to exit quiescence and transdifferentiate into CySCs (Hetie, Cell Reports 2014). This study demonstrated that CySCs non-autonomously maintain niche cells, but the identity of the factors that regulate this process are still not known. Through an RNAi screen, we identified the secreted Activin antagonist Follistatin (Fs) as a CySC-produced factor required to maintain niche cells. Upon depletion of Fs from CySCs, niche cells are progressively and ultimately completely lost, followed by a loss of GSCs and a collapse of spermatogenesis. These data indicate that CySC-produced Fs protects niche cells from local Activin ligands. Consistent with this finding, autonomous stimulation of Activin signaling in niche cells causes all of them to transdifferentiate into fully functional CySCs. These changes of cell identity require the activity of the Jun N-terminal Kinase pathway. Interestingly, we also find that the levels of Fs decrease with age and that the normal age-related loss of niche cells can be rescued either by mis-expressing Fs or by downregulating the Activin pathway in niche cells. We also show that in CySCs, expression of Fs is positively regulated by the Dp/E2f1 transcription factor complex. Depletion of Dp/E2f1 from CySCs results in the non-autonomous loss of all niche cells. Importantly, ectopic mis-expression of Fs in CySCs depleted for Dp/E2f1 fully rescues the niche loss phenotype. These results support a model in which TGFß/Activin signaling, in synergy with JNK, acts as a switch that triggers in niche cells a regenerative response aimed to replenish lost CySCs, at the cost of reducing the niche population. We also propose that this mechanism underlies the age-related loss of niche cells.