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.
Adult stem cells are believed to be depleted from many tissues during aging, which eventually manifests as aging in the organism as a whole. Thus, understanding what causes this depletion has far-reaching clinical implications for tissue repair, cancer, and general aging. Our research will investigate how stem cells age in the Drosophila testis and how this ultimately manifests as functional decline at the cellular and tissue level.
|Lu, Kevin L; Nelson, Jonathan O; Watase, George J et al. (2018) Transgenerational dynamics of rDNA copy number in Drosophila male germline stem cells. Elife 7:|
|Lu, Kevin L; Yamashita, Yukiko M (2017) Germ cell connectivity enhances cell death in response to DNA damage in the Drosophila testis. Elife 6:|
|Lu, Kevin; Jensen, Lindy; Lei, Lei et al. (2017) Stay Connected: A Germ Cell Strategy. Trends Genet 33:971-978|