Socs36E Controls Niche Competition by Repressing MAPK Signaling in the Drosophila Testis

Abstract

The Drosophila testis is a well-established system for studying stem cell self-renewal and competition. In this tissue, the niche supports two stem cell populations, germ line stem cells (GSCs), which give rise to sperm, and somatic stem cells called cyst stem cells (CySCs), which support GSCs and their descendants. It has been established that CySCs compete with each other and with GSCs for niche access, and mutations have been identified that confer increased competitiveness to CySCs, resulting in the mutant stem cell and its descendants outcompeting wild type resident stem cells. Socs36E, which encodes a negative feedback inhibitor of the JAK/STAT pathway, was the first identified regulator of niche competition. The competitive behavior of Socs36E mutant CySCs was attributed to increased JAK/STAT signaling. Here we show that competitive behavior of Socs36E mutant CySCs is due in large part to unbridled Mitogen-Activated Protein Kinase (MAPK) signaling. In Socs36E mutant clones, MAPK activity is elevated. Furthermore, we find that clonal upregulation of MAPK in CySCs leads to their outcompetition of wild type CySCs and of GSCs, recapitulating the Socs36E mutant phenotype. Indeed, when MAPK activity is removed from Socs36E mutant clones, they lose their competitiveness but maintain self-renewal, presumably due to increased JAK/STAT signaling in these cells. Consistently, loss of JAK/STAT activity in Socs36E mutant clones severely impairs their self-renewal. Thus, our results enable the genetic separation of two essential processes that occur in stem cells. While some niche signals specify the intrinsic property of self-renewal, which is absolutely required in all stem cells for niche residence, additional signals control the ability of stem cells to compete with their neighbors. Socs36E is node through which these processes are linked, demonstrating that negative feedback inhibition integrates multiple aspects of stem cell behavior.

Direct control of somatic stem cell proliferation by theDrosophilatestis stem cell niche

“…Third, the micromanagement model we propose will still be a truncation of the true regulatory network. For example, we already know that different aspects of stem cell activity in the testis are coupled by competition (Amoyel et al, 2016;Issigonis et al, 2009;Singh et al, 2016). This makes it difficult to analyze loss of function conditions in our model system, as affected cells are eliminated by differentiation before they can be studied.…”

JAK/STAT signaling in stem cells and regeneration: fromDrosophilato vertebrates

“…Both Zfh1 and Chinmo are required autonomously for niche residence of CySCs; CySCs lacking either gene rapidly differentiate (Flaherty et al, 2010;Leatherman and Dinardo, 2008). The role of CySCs in supporting GSCs is also endowed by JAK/STAT signaling through zfh1 and chinmo, but not by other CySC self-renewal pathways (Albert et al, 2018;Amoyel et al, 2014aAmoyel et al, , 2016aAmoyel et al, , 2013Flaherty et al, 2010;Dinardo, 2008, 2010). Ectopic activation of Stat92E or mis-expression of zfh1 or chinmo in CySCs is sufficient to expand both CySC and GSC pools.…”

Somatic stem cell differentiation is regulated by PI3K/Tor signaling in response to local cues

“…CySCs require JAK/STAT signaling for self-renewal, and the hub produces the JAK/STAT pathway ligand Unpaired (Upd) to maintain CySCs (Kiger et al, 2001;Leatherman and Dinardo, 2008;Tulina and Matunis, 2001). Additionally, CySCs require Hedgehog, Hippo, Slit/Robo and MAPK signals in order to remain at the niche and compete for space (Amoyel et al, 2013(Amoyel et al, , 2014(Amoyel et al, , 2016Issigonis et al, 2009;Michel et al, 2012;Stine et al, 2014). In addition to intercellular signaling, many autonomous factors maintain CySCs, particularly the transcription factor Zfh1, which marks the CySC population (Leatherman and Dinardo, 2008).…”