CncC/Keap1 signaling pathway in the regulation of intestinal stem cells in Drosophila

Thesis (Ph. D.)--University of Rochester. Dept. of Biology, 2012.Organisms are faced with the challenge of maintaining tissue homeostasis despite various environmental and intracellular assaults that damage cells. Programmed cell death can eliminate cells that are no longer contributing to the proper function of a tissue. However, apoptosis without concomitant cell replacement over time would result in the loss of tissue and is not ideal for the overall health of the organism. Therefore, regenerative processes are critical in delaying the loss of tissue homeostasis that is characteristic of aging animals. In the adult metazoan, this goal is accomplished by pluripotent stem cells. How the regenerative capacity of stem cells changes in aging animals is the subject of intense investigation. The recent discovery of intestinal stem cells (ISCs) in the posterior midgut of Drosophila melanogaster has introduced this organism as a genetically amenable model for such studies. Antioxidant defenses and cytoprotective processes are believed to be critical for the maintenance of stem cell function. Here I present work which characterizes the role of a stress-responsive signaling pathway, NF-E2-related factor 2 [Nrf2(CncC in Drosophila)], in stem cell maintenance and regeneration of the intestinal epithelium of Drosophila. Using genetic and cellular biology approaches, I found Nrf2 to be a key regulator of ISC quiescence and also established cellular redox state, in general, as important for the control of ISC proliferation. Additional work presented in this dissertation will explore mechanisms of CncC regulation in ISCs in response to stress and a potential interaction between the CncC and Jun-N-terminal kinase (JNK) pathways. Furthermore, ISC proliferation will be investigated to determine the dynamics of stem cell quiescence in the adult intestinal epithelium. Together, these data demonstrate the importance of cellular redox state in the control of cellular processes and reveal a novel mechanism of stem cell and stem cell progenitor regulation by Nrf2