MicroRNA profiling identifies novel regulators of stem cell function in the adult Drosophila intestine

Precise control of stem cell activity is critical to maintain homeostasis and regenerative capacity of adult tissues and limit proliferative syndromes. Hence, stem cell-specific complex regulatory networks exist to exquisitely maintain gene expression and adapt it to tissue demand, allowing precise control of self-renewal, fate commitment and differentiation of developing and adults cell lineages. Some of the essential and conserved regulatory components that fine-tune gene expression are microRNAs, which post-transcriptionally regulate stability and translation of messengers. microRNAs have been identified as critical stem cell regulators across stem cell populations and organisms. Here, we report the profiling of microRNAs expressed in stem cells and their immediate daughter cells in the Drosophila adult intestine. Our analysis identifies multiple microRNAs that can be reliably detected in these sorted progenitor cells. A few of these have been reported to control fly intestinal stem cells, but most have yet to be investigated in this lineage. To validate the relevance of our analysis, we chose to characterize the phenotypes associated with genetic manipulations of two of these microRNAs, mir-31a and mir-34, which are conserved in other organisms but whose function has not been investigated in the Drosophila midgut. We found that mir-31a acts as an anti-proliferation factor and is important for the re-entry of ISC into quiescence after tissue damage. Additionally, we demonstrate that mir-34 is essential for ISC proliferation, but its over-expression also prevents proliferation, highlighting the complexity of microRNA-mediated control of stem cell function. Altogether, our work establishes a new critical resource to investigate the mechanisms that control stem cell proliferation and intestinal differentiation under homeostatic conditions, in response to tissue damage, or during epithelial transformation and aging.