Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration
Program in Molecular Medicine
Animals; Bleomycin; Cell Differentiation; Cell Proliferation; DNA-Binding Proteins; Dextran Sulfate; Drosophila; Drosophila Proteins; Female; Green Fluorescent Proteins; Intestines; Intracellular Signaling Peptides and Proteins; Janus Kinases; Nuclear Proteins; Protein-Serine-Threonine Kinases; RNA Interference; RNA, Small Interfering; Receptor, Epidermal Growth Factor; Receptors, Invertebrate Peptide; STAT Transcription Factors; Signal Transduction; Stem Cells; Trans-Activators; Transcription Factors; Transcription, Genetic
Cell Biology | Cells | Cellular and Molecular Physiology | Digestive System
Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis, and their proliferation and differentiation speed up in order to meet the demand for replenishing the lost cells in response to injury. Several signaling pathways including JAK-STAT, EGFR and Hippo (Hpo) pathways have been implicated in damage-induced ISC proliferation, but the mechanisms that integrate these pathways have remained elusive. Here, we demonstrate that the Drosophila homolog of the oncoprotein Myc (dMyc) functions downstream of these signaling pathways to mediate their effects on ISC proliferation. dMyc expression in precursor cells is stimulated in response to tissue damage, and dMyc is essential for accelerated ISC proliferation and midgut regeneration. We show that tissue damage caused by dextran sulfate sodium feeding stimulates dMyc expression via the Hpo pathway, whereas bleomycin feeding activates dMyc through the JAK-STAT and EGFR pathways. We provide evidence that dMyc expression is transcriptionally upregulated by multiple signaling pathways, which is required for optimal ISC proliferation in response to tissue damage. We have also obtained evidence that tissue damage can upregulate dMyc expression post-transcriptionally. Finally, we show that a basal level of dMyc expression is required for ISC maintenance, proliferation and lineage differentiation during normal tissue homeostasis.
DOI of Published Version
Cell Res. 2013 Sep;23(9):1133-46. doi: 10.1038/cr.2013.101. Epub 2013 Jul 30. Link to article on publisher's site
Ren, Fangfang; Shi, Qing; Chen, Yongbin; Jiang, Alice; Ip, Y. Tony; Jiang, Huaqi; and Jiang, Jin, "Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration" (2013). University of Massachusetts Medical School Faculty Publications. 600.