Tis11 mediated mRNA degradation regulates intestinal stem cell quiescence

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): The control of epithelial tissue various stressful conditions, to identify the mechanism of Tis11 function in ISCs, and to establish whether Tis11 activity in ISCs influences age-related changes in homeostasis of the epithelium. Homeostasis requires accurate control of stem cell proliferation in response to a variety of stimuli. A critica aspect of this regulation is the return of stem cells to a quiescent state after a transient burst f regenerative activity. Here, I propose experiments designed to elucidate regulatory mechanisms that control this recovery. I use the Drosophila posterior midgut epithelium as a model to establish the function of the mRNA degradation pathway in stem cell recovery. I have identified the RNA binding protein Tis11 as an inhibitor of stem cell proliferation that is specifically expressed in stem cells. Strikingly, I find that Tis 11 is required for recovery of a quiescent stae in the intestinal epithelium after a mild challenge. I now propose to extend this work to test to te hypothesis that Tis11 is critical for the recovery of quiescent ISCs under times of stressed induced proliferation. PUBLIC HEALTH RELEVANCE: Accurate control of stem cell activity is critical for tissue homeostasis. The applicant will analyze the regulation of stem cell quiescence using the Drosophila midgut epithelium as a genetically accessible model system. Through genetic and biochemical studies, the applicant will test the hypothesis that the RNA binding factor Tis11 plays a central role in the control of quiescence in the intestinal stem cells, and that this regulation is critical to prevent age-related changes in stem cell function.