ABSTRACT
Somatic adult stem cell lineages in high-turnover tissues are under tight gene regulatory control. Like its mammalian counterpart, the Drosophila intestine precisely adjusts the rate of stem cell division with the onset of differentiation based on physiological demand. Although Notch signaling is indispensable for these decisions, the regulation of Notch activity that drives the differentiation of stem cell progenies into functional, mature cells is not well understood. Here, we report that commitment to the terminally differentiated enterocyte (EC) cell fate is under microRNA control. We show that an intestinally enriched microRNA, miR-956, fine-tunes Notch signaling activity specifically in intermediate, enteroblast (EB) progenitor cells to control EC differentiation. We further identify insensitive mRNA as a target of miR-956 that regulates EB/EC ratios by repressing Notch activity in EBs. In summary, our study highlights a post-transcriptional gene-regulatory mechanism for controlling differentiation in an adult intestinal stem cell lineage.
Subject(s)
Drosophila Proteins , MicroRNAs , Animals , Drosophila/genetics , Drosophila Proteins/genetics , Receptors, Notch/genetics , Drosophila melanogaster/physiology , MicroRNAs/genetics , Intestines , RNA, Messenger , Mammals/geneticsABSTRACT
Since the widespread discovery of microRNAs (miRNAs) 20 years ago, the Drosophila melanogaster model system has made important contributions to understanding the biology of this class of noncoding RNAs. These contributions are based on the amenability of this model system not only for biochemical analysis but molecular, genetic, and cell biological analyses as well. Nevertheless, while the Drosophila genome is now known to encode 258 miRNA precursors, the function of only a small minority of these have been well characterized. In this review, we summarize the current resources and methods that are available to study miRNA function in Drosophila with a particular focus on the large-scale resources that enable systematic analysis. Application of these methods will accelerate the discovery of ways that miRNAs are embedded into genetic networks that control basic features of metazoan cells.
Subject(s)
Drosophila , MicroRNAs , Animals , Computational Biology/methods , Drosophila/genetics , Drosophila melanogaster/genetics , Gene Regulatory Networks , MicroRNAs/chemistry , MicroRNAs/geneticsABSTRACT
Adult organisms must sense and adapt to environmental fluctuations. In high-turnover tissues such as the intestine, these adaptive responses require rapid changes in gene expression that, in turn, likely involve posttranscriptional gene control. However, intestinal-tissue-specific microRNA (miRNA)-mediated regulatory pathways remain unexplored. Here, we report the role of an intestinal-specific miRNA, miR-958, that non-cell autonomously regulates stem cell numbers during tissue homeostasis and regeneration in the Drosophila adult midgut. We identify its downstream target cabut, the Drosophila ortholog of mammalian KLF10/11 transcription factors, which mediates this miR-958 function by promoting paracrine enterocyte-to-stem-cell bone morphogenetic protein (BMP) signaling. We also show that mature miR-958 levels transiently decrease in response to stress and that this decrease is required for proper stem cell expansion during tissue regeneration. In summary, we have identified a posttranscriptional mechanism that modulates BMP signaling activity within Drosophila adult intestinal tissue during both normal homeostasis and tissue regeneration to regulate intestinal stem cell numbers.
