Nucleolar fragmentation in Drosophila germline stem cells during aging

 描述(申请人提供)：尽管已经证明重复的不对称分裂可以导致“年龄”因素的不对称分离，这些因素导致酵母等单细胞生物体中的复制衰老，但尚不清楚类似的机制是否会导致多细胞生物体中不对称分裂的干细胞的衰老和枯竭。为了深入了解这个问题，我们使用果蝇睾丸作为模型系统来研究衰老过程中干细胞的不对称分裂。我们发现生殖系干细胞(GSCs)经历了渐进性的核仁碎裂，这是发芽酵母不对称分裂时rDNA不稳定的标志。众所周知，这会导致老化酵母细胞的复制衰老。因此，我们假设rDNA重复序列的不稳定也会导致果蝇雄性GSCs在不对称分裂过程中的细胞衰老，表现为无法随着年龄的增长维持生殖系的动态平衡。为了验证我们的假设，我们将确定GSC中核仁碎裂的机制。此外，我们还将研究生殖系核仁碎裂对后代的影响。如果我们的假设是正确的，它将描述一种以前未描述的干细胞功能障碍的细胞内在机制，并对有机体随年龄保持组织内稳态的能力有影响。

 DESCRIPTION (provided by applicant): Though it has been shown that repeated asymmetric division can result in an asymmetric segregation of "age" factors that contribute to replicative senescence in unicellular organisms like yeast, it's unknown whether a similar mechanism contributes to the senescence and depletion of asymmetrically-dividing stem cells in multicellular organisms. To gain insight into this question, we have used the Drosophila testis as a model system to study asymmetric stem cell division during aging. We find that germline stem cells (GSCs) undergo progressive nucleolar fragmentation, which is a hallmark of rDNA destabilization in budding yeast as it divides asymmetrically. This is known to result in replicative senescence of aging yeast cells. Thus, we hypothesize that destabilization of rDNA repeats also causes cellular senescence in Drosophila male GSCs during asymmetric division, which manifests as an inability to maintain germline homeostasis with age. To test our hypothesis, we will determine the mechanism of nucleolar fragmentation in GSCs. Additionally; we will investigate the effect of germline nucleolar fragmentation on subsequent generations. If our hypothesis is true, it would describe a previously uncharacterized cell-intrinsic mechanism of stem cell dysfunction, and have implications for an organism's ability to maintain tissue homeostasis with age.