Abstract
Exhaustion of stem cells is a hallmark of aging. In the Drosophila testis, dedifferentiated germline stem cells (GSCs) derived from spermatogonia increase during lifespan, leading to the model that dedifferentiation counteracts the decline of GSCs in aged males. To test this, we blocked dedifferentiation by mis-expressing the differentiation factor bag of marbles (bam) in spermatogonia while lineage-labeling these cells. Strikingly, blocking bam-lineage dedifferentiation under normal conditions in virgin males has no impact on the GSC pool. However, in mated males or challenging conditions, inhibiting bam-lineage dedifferentiation markedly reduces the number of GSCs and their ability to proliferate and differentiate. We find that bam-lineage derived GSCs have significantly higher proliferation rates than sibling GSCs in the same testis. We determined that Jun N-terminal kinase (JNK) activity is autonomously required for bam-lineage dedifferentiation. Overall, we show that dedifferentiation provides a mechanism to maintain the germline and ensure fertility under chronically stressful conditions.
Highlights
A robust stem cell pool is critical to the maintenance of highly proliferative tissues during an organism’s lifetime
In order to study the contribution of dedifferentiation to the maintenance of the germline stem cells (GSCs) pool, we lineage-traced spermatogonial cells
For reasons unknown to us and observed by another group (Cheng et al, 2008), some somatic support cells are labeled for realtime and lineage bam expression (Figure 1B and Figure 1—figure supplement 2C). We note that this methodology will likely not label all dedifferentiating germ cells, as it has been speculated that gonialblasts and 2-cell spermatogonia can revert to become GSCs
Summary
A robust stem cell pool is critical to the maintenance of highly proliferative tissues during an organism’s lifetime. (B–E) Representative images of the testis stem cell niche in control bam-Gal, UAS-LacZ (bam > LacZ, B, C) or bam-Gal, UAS-bam (bam > bam, D, E), where we blocked bam-lineage dedifferentiation at 0 days and 45 days under normal aging conditions. Upon silencing of these triggers, spermatogonia break apart, migrate back to the niche, outcompete the resident CySCs and become functional GSCs by transducing JAK/STAT signals and repressing bam expression (Brawley and Matunis, 2004; Sheng et al, 2009; Sheng and Matunis, 2011) These studies revealed that the 8-cell spermatogonial cyst is the oldest stage still competent to dedifferentiate. We have developed a methodology that enabled us to inhibit dedifferentiation of bam-expressing, 4- and 8-cell spermatogonial cysts without apparent side effects, while at the same time lineage-tracing these cells. By inhibiting JNK activity in bam-expressing spermatogonia, we demonstrate that this pathway is essential for dedifferentiation of these cells
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