Niche signaling promotes stem cell survival in the Drosophila testis via the JAK–STAT target DIAP1

Abstract

Tissue-specific stem cells are thought to resist environmental insults better than their differentiating progeny, but this resistance varies from one tissue to another, and the underlying mechanisms are not well-understood. Here, we use the Drosophila testis as a model system to study the regulation of cell death within an intact niche. This niche contains sperm-producing germline stem cells (GSCs) and accompanying somatic cyst stem cells (or CySCs). Although many signals are known to promote stem cell self-renewal in this tissue, including the highly conserved JAK-STAT pathway, the response of these stem cells to potential death-inducing signals, and factors promoting stem cell survival, have not been characterized. Here we find that both GSCs and CySCs resist cell death better than their differentiating progeny, under normal laboratory conditions and in response to potential death-inducing stimuli such as irradiation or starvation. To ask what might be promoting stem cell survival, we characterized the role of the anti-apoptotic gene Drosophila inhibitor of apoptosis 1 (diap1) in testis stem cells. DIAP1 protein is enriched in the GSCs and CySCs and is a Jak-STAT target. diap1 is necessary for survival of both GSCs and CySCs, and ectopic up-regulation of DIAP1 in somatic cyst cells is sufficient to non-autonomously rescue stress-induced cell death in adjacent differentiating germ cells (spermatogonia). Altogether, our results show that niche signals can promote stem cell survival by up-regulation of highly conserved anti-apoptotic proteins, and suggest that this strategy may underlie the ability of stem cells to resist death more generally.

JAK/STAT signalling mediates cell survival in response to tissue stress

“…So far, only isolated studies have implicated JAK/STAT in cell survival (Betz et al, 2008;Hasan et al, 2015;Guarner et al, 2014;Ohayon et al, 2009). For example, the apoptosis inhibitor IAP has been suggested to be a positively regulated target of Stat92E, protecting cells from apoptosis (Betz et al, 2008;Hasan et al, 2015). We identify the JAK/STAT effector Zfh2 as a potential repressor of kay and hid activity -a molecular pathway expected to restrain excessive JNK-activity and induction of apoptosis (Fig.…”

“…However, continuous overexpression of Upd can also induce apoptosis (not shown) and, thus potentially also sustained JNK-dependent compensatory proliferation, driving tissue growth. So far, only isolated studies have implicated JAK/STAT in cell survival (Betz et al, 2008;Hasan et al, 2015;Guarner et al, 2014;Ohayon et al, 2009). For example, the apoptosis inhibitor IAP has been suggested to be a positively regulated target of Stat92E, protecting cells from apoptosis (Betz et al, 2008;Hasan et al, 2015).…”

“…In fly tumours, STATresponsive enhancers have been mapped (Davie et al, 2015), but few target genes regulating tissue size have been described (Tsai and Sun, 2004;Betz et al, 2008;Hasan et al, 2015). However, several studies suggest that developmental functions of JAK/STAT are mediated by the transcriptional repressors Chinmo (Flaherty et al, 2010), Zfh1 (Ohayon et al, 2009;Leatherman and Dinardo, 2008) and Zfh2 (Perea et al, 2013;Guarner et al, 2014;Ayala-Camargo et al, 2013).…”

Intestinal stem cell ablation reveals differential requirements for survival in response to chemical challenge

“…Previous studies have attempted complete ablation of ISCs by expressing pro-apoptotic genes, which has proved challenging due to an apparent resistance of some stem cells to apoptosis [5][40][41][42] or embryonic or larval death due to leaky expression of pro-apoptotic factors (data not shown). Our strategy to ablate ISCs/EBs by depleting Hdc supports a model wherein ISCs are largely dispensable for intestinal function and fly survival in non-challenged conditions.…”

Polycomb Group Gene E(z) Is Required for Spermatogonial Dedifferentiation in Drosophila Adult Testis

“…However, we detected no lysotracker-positive E(z) mutant GSCs (N=106, Supplementary Figure 2c), indicating increased cell death to be an unlikely cause of their loss. Previous studies have shown that normal GSCs have unique protective mechanisms against cell death [63–65]. Loss of E(z) does not seem to abrogate this protection.…”