Biology and Biomedical Sciences: Developmental, Regenerative and Stem Cell Biology
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
In the C. elegans germline, stem cells make a decision to retain the germline proliferative cell fate or differentiate by entering meiosis. Importantly, this decision must be coordinated with progression through the mitotic cell cycle. Previous work has shown that the conserved GLP-1/Notch signaling pathway promotes the proliferative fate while two downstream and redundant pathways are repressed by GLP-1 and promote entry into meiosis: the GLD-1 and GLD-2 pathways. To better understand how the switch to enter meiosis is coordinated with progression through the mitotic cell cycle, I investigated mitotic cell cycle progression among germline proliferative cells. Proliferative cells cycle continuously and have an atypical cell cycle structure in which the G1 phase is omitted. These features of mitotic cell cycle progression are likely explained by continuous CDK-2-CYE-1 activity throughout the cell cycle. In addition to driving cell cycle progression, cdk-2 and cye-1 are also important for promoting the proliferative fate. This suggests that CDK-2-CYE-1 may act to coordinate mitotic cell cycle progression with the proliferative cell fate. While GLP-1 promotes the proliferative fate, GLP-1 does not appear to influence cell cycle rate, suggesting that GLP-1 only regulates proliferative fate, and not mitotic cell division. Whereas CDK-2-CYE-1 may coordinate cell fate and mitotic cell cycle progression, other signaling pathways, such as the GLP-1 pathway, may only regulate cell fate. To further investigate how the switch to meiosis is coordinated with cell cycle progression, I analyzed the spatial and temporal pattern of meiotic entry among proliferative zone cells following induced loss of glp-1. This analysis provided two important conclusions. First, the response of mitotically dividing proliferative zone cells appears to depend on their position in the cell cycle, and proliferative cells likely make the switch to meiosis prior to the initiation of S-phase. Second, actively cycling proliferative zone cells did not appear to display a differential response to loss of glp-1 other than the meiotic entry timing variation due to cell cycle position. This supports the hypothesis that mitotically cycling proliferative zone cells are developmentally equivalent and that preprogrammed transit amplifying divisions do not occur following loss of GLP-1 activity.
Fox, Paul, "Mitotic cell cycle progression and differentiation of germline stem cells in Caenorhabditis elegans" (2010). All Theses and Dissertations (ETDs). 116.