Author ORCID Identifier

0000-0003-2161-4645

Date of Graduation

5-2019

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Swathi Arur

Committee Member

Dr. Richard Behringer

Committee Member

Dr. Jichao Chen

Committee Member

Dr. Francesca Cole

Committee Member

Dr. Zheng Zhou

Abstract

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. Caenorhabditis elegans 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 gsk-3. Loss of gsk-3 inhibits S phase entry and progression through transcriptional down-regulation of cdk-2. Since metabolic signaling regulates gsk-3, 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.

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 cdk-1regulation. I find that cdk-1 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 C. elegans 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.

Keywords

C. elegans, Nutrition, Germ cells, Cell cycle, Stem cells, Plasticity, TOR Signaling, Insulin Signaling, GSK3, Cell cycle arrest

Available for download on Thursday, October 03, 2019

Share

COinS