Platiscity of C. Elegans Germline Stem Cells Under Nutritional and Metabolic Stress

<p>Stem cells are integral for tissue maintenance and fertility. Therefore, understanding how stem cells are regulated under stress is imperative. When confronted with acute starvation, stem cells must conserve energy and metabolites to cope with the lack of an external source. <em>Caenorhabditis elegans</em> germline stem cells (GSCs) are an excellent model for studying stem cell properties and regulation as they can divide throughout the life of the organism. While GSCs are an adult stem cell population, their cell cycle structure more closely mimics mouse and human embryonic stem cells with short G1 and long S phases. In this thesis, I report that adult GSCs regulate both the G1 and G2 phases to maintain their unique cell cycle structure. I find that the short G1 is promoted by the metabolic regulator <em>gsk-3</em>. Loss of <em>gsk-3</em> inhibits S phase entry and progression through transcriptional down-regulation of <em>cdk-2</em>. Since metabolic signaling regulates <em>gsk-3</em>, I propose that controlling G1 progression may allow the cells to buffer metabolic stress. These observations also made me wonder how stem cells would respond to the extreme conditions of acute starvation.</p> <p>Adult GSCs are known to undergo a cell cycle arrest during acute starvation, so I investigated the mechanisms and cellular behaviors underlying this arrest. I find that acute starvation causes a reversible G2 arrest which is independent of the canonical DNA damage signaling arrest. Instead, this reversible G2 arrest is regulated by the Insulin signaling and TOR signaling pathways. Detailed investigation of the TOR signaling axis revealed that the G2 arrest is partially dependent on stress kinase signaling, and is mediated by <em>cdk-1</em>regulation. I find that <em>cdk-1</em> is both translationally and post-translationally regulated to impose the strong starvation-induced G2 arrest. Together, these data reveal novel paradigms through which adult GSCs maintain tissue homeostasis and regenerate tissues to respond to either chronic metabolic stress or acute nutritional deprivation. Given the cell cycle structure conservation between <em>C. elegans</em> GSCs and mammalian embryonic stem cells, I propose that gap phase regulation may also drive stem cell homeostasis in mouse and human embryonic stem cells in response to environmental and metabolic perturbation.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2019

Authors dc:creator

• Trimmer, Kenneth
• <p><a href="http://orcid.org/0000-0003-2161-4645" target="_blank">0000-0003-2161-4645</a></p>

Contributors dc:contributor

• Dr. Swathi Arur
• Dr. Richard Behringer
• Dr. Jichao Chen

• C. elegans
• Nutrition
• Germ cells
• Cell cycle
• Stem cells
• Plasticity
• TOR Signaling
• Insulin Signaling
• GSK3
• Cell cycle arrest
• Cell Biology
• Developmental Biology
• Medicine and Health Sciences
• Molecular, Genetic, and Biochemical Nutrition
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/922

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1969