Upregulated TNF/Eiger signaling mediates stem cell recovery and tissue homeostasis during nutrient resupply in Drosophila testis

Abstract

Stem cell activity and cell differentiation is robustly influenced by the nutrient availability in the gonads. The signal that connects nutrient availability to gonadal stem cell activity remains largely unknown. In this study, we show that tumor necrosis factor Eiger (Egr) is upregulated in testicular smooth muscles as a response to prolonged protein starvation in Drosophila testis. While Egr is not essential for starvation-induced changes in germline and somatic stem cell numbers, Egr and its receptor Grindelwald influence the recovery dynamics of somatic cyst stem cells (CySCs) upon protein refeeding. Moreover, Egr is also involved in the refeeding-induced, ectopic expression of the CySC self-renewal protein and the accumulation of early germ cells. Egr primarily acts through the Jun N-terminal kinase (JNK) signaling in Drosophila . We show that inhibition of JNK signaling in cyst cells suppresses the refeeding-induced abnormality in both somatic and germ cells. In conclusion, our study reveals both beneficial and detrimental effects of Egr upregulation in the recovery of stem cells and spermatogenesis from prolonged protein starvation.

The Emerging Roles of JNK Signaling in Drosophila Stem Cell Homeostasis

“…By contrast, chronic starvation of more than two weeks induces Egf/TNFα in muscle, which then leads to dysregulation of the germline and soma and reduced fertility [41]. These results indicate that acute JNK is not deleterious to tissue homeostasis [33,40,41], but that chronic pathway activation perturbs tissue function [35]. The second consideration is the level of pathway activation induced by the stress.…”

“…In the testis, protein starvation reduces the number of GSCs and CySCs [ 33 , 39 , 40 ]. GSC or CySC number can be restored after five or two days, respectively, of refeeding with standard food [ 33 , 39 , 41 ]. Interestingly, the maintenance of the reduced GSC pool during starvation depends upon JNK signaling.…”

“…In addition to protein starvation, mating is another JNK-related source of stress in the Drosophila testis [ 33 , 35 , 41 ]. Prolonged mating (occurring for more than five weeks) in aged flies induces the expression of Egr/TNFα in the muscle sheath, which then accumulates in the testis lumen, and the upregulation of Grnd/TNFR in somatic support cells ( Figure 2 C).…”

“…The JNK pathway is critical for the recovery of somatic and germline lineages after stress ( Figure 2 D). After starvation, JNK is activated in CySCs by muscle-produced Egr/TNFα acting on Grnd/TNFR [ 41 ]. This autonomous JNK activation in CySCs is necessary for recovery of the somatic lineage after starvation and thus for continued gametogenesis.…”

“…For instance, acute starvation of three to six days does not induce Egf/TNFα in muscle cells; the CySC pool fully recovers after the termination of stress and homeostasis is restored. By contrast, chronic starvation of more than two weeks induces Egf/TNFα in muscle, which then leads to dysregulation of the germline and soma and reduced fertility [ 41 ]. These results indicate that acute JNK is not deleterious to tissue homeostasis [ 33 , 40 , 41 ], but that chronic pathway activation perturbs tissue function [ 35 ].…”