title: Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration.
abstract: 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.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Ren
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Chen
authors.forename: Alice
authors.initials: A
authors.lastname: Jiang
authors.forename: Y Tony
authors.initials: YT
authors.lastname: Ip
authors.forename: Huaqi
authors.initials: H
authors.lastname: Jiang
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D018010:Receptors, Invertebrate Peptide / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D001761:Bleomycin; D004268:DNA-Binding Proteins; D016264:Dextran Sulfate; D029721:Drosophila Proteins; D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053612:Janus Kinases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D018010:Receptors, Invertebrate Peptide; D050791:STAT Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C102284:Myc protein, Drosophila; C503814:Yki protein, Drosophila; C066532:Egfr protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
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