Role of Tis11 in Drosophila Intestinal Stem Cell Function

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2016.Many tissues contain a population of adult stem cells whose function is precisely regulated to promote tissue homeostasis. Tissues whose stem cells fail to respond to regenerative cues atrophy, while stem cells that are continuously proliferating can promote hyperproliferative diseases. Therefore, an understanding of the precise regulation of adult stem cell function will lead to insights on how these adult stem cells function to maintain healthy tissues. Many adult stem cells exhibit a proliferative plasticity where their proliferation rates dynamically increase in response to damage to their resident tissue. For these adult stem cells, a critical part of maintaining tissue homeostasis is the reacquisition of basal proliferation rates after the tissue has been repaired. Currently, little is known about the molecular mechanisms that promote the restoration of basal proliferation rates. Here I show that Tis11, an Adenine-uridine Rich Element (ARE) binding protein that promotes mRNA degradation, is required to re-establish basal proliferation rates in the Drosophila intestinal epithelium after regenerative episodes. Through lineage tracing techniques and detailed kinetic studies of the ISC regenerative response, I find Tis11 functions cell autonomously to limit ISC proliferation. I also find that Tis11 is dynamically regulated, as its expression and activity is increased in ISCs during tissue repair. Furthermore, promoting defects in mRNA stability independent of Tis11 activity also limits ISC proliferation rates. This observation along with the finding that clone size of Tis11 gain-of-function ISCs can be rescued by simultaneously making them deficient in RNA degradation support that Tis11 is functioning in ISCs by promoting mRNA decay. Based on transcriptome and RNA immunoprecipitation data, I propose that Tis11 activation represents an integral part of a negative feedback mechanism that limits the expression of several components of pro-mitotic signaling pathways. Our results identify Tis11 mediated mRNA decay as a new, evolutionarily conserved mechanism of re-establishing the basal proliferation rates of stem cells in regenerating tissues