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Hippo, TGF-β, and Src-MAPK pathways regulate transcription of the upd3 cytokine in Drosophila enterocytes upon bacterial infection
- Source :
- PLoS Genetics, PLoS Genetics, 2017, 13, pp.e1007091. ⟨10.1371/journal.pgen.1007091⟩, PLoS Genetics, Public Library of Science, 2017, 13, pp.e1007091. ⟨10.1371/journal.pgen.1007091⟩, PLoS Genetics, Vol 13, Iss 11, p e1007091 (2017)
- Publication Year :
- 2017
- Publisher :
- Public Library of Science (PLoS), 2017.
-
Abstract
- Cytokine signaling is responsible for coordinating conserved epithelial regeneration and immune responses in the digestive tract. In the Drosophila midgut, Upd3 is a major cytokine, which is induced in enterocytes (EC) and enteroblasts (EB) upon oral infection, and initiates intestinal stem cell (ISC) dependent tissue repair. To date, the genetic network directing upd3 transcription remains largely uncharacterized. Here, we have identified the key infection-responsive enhancers of the upd3 gene and show that distinct enhancers respond to various stresses. Furthermore, through functional genetic screening, bioinformatic analyses and yeast one-hybrid screening, we determined that the transcription factors Scalloped (Sd), Mothers against dpp (Mad), and D-Fos are principal regulators of upd3 expression. Our study demonstrates that upd3 transcription in the gut is regulated by the activation of multiple pathways, including the Hippo, TGF-β/Dpp, and Src, as well as p38-dependent MAPK pathways. Thus, these essential pathways, which are known to control ISC proliferation cell-autonomously, are also activated in ECs to promote tissue turnover the regulation of upd3 transcription.<br />Author summary Tissue regeneration is a fundamental process that maintains the integrity of the intestinal epithelium when faced with chemical or microbial stresses. In both healthy and diseased conditions, pro-regenerative cytokines function as central coordinators of gut renewal, linking inflammation to stem cell activity. In Drosophila, the upstream events that stimulate the production of the primary cytokine Unpaired 3 (Upd3) in response to indigenous or pathogenic microbes have yet to be elucidated. In this study, we demonstrate that upd3 expression is driven in different cell types by separate microbe-responsive enhancers. In enterocytes (ECs), cytokine induction relies on the Yki/Sd, Mad/Med, and AP-1 transcription factors (TFs). These TF complexes are activated downstream of the Hippo, TGF-β and Src-MAPK pathways, respectively. Inhibiting these pathways in ECs impairs upd3 transcription, which in turn blocks intestinal stem cell proliferation and reduces the survival rate of adult flies following enteric infections. Altogether, our study identifies the major microbe-responsive enhancers of the upd3 gene and sheds light on the complexity of the gene regulatory network required in ECs to regulate tissue homeostasis and stem cell activity in the digestive tract.
- Subjects :
- Male
0301 basic medicine
MAPK/ERK pathway
Cancer Research
DBG
Physiology
[SDV]Life Sciences [q-bio]
Gene Expression
Apoptosis
Biochemistry
RNA interference
Transforming Growth Factor beta
Transcription (biology)
Immune Physiology
Medicine and Health Sciences
Transcriptional regulation
Drosophila Proteins
Gene Regulatory Networks
Genetics (clinical)
Regulation of gene expression
Genetics
Innate Immune System
Cell Death
Stem Cells
Transcriptional Control
Drosophila Melanogaster
EQYY
Intracellular Signaling Peptides and Proteins
Eukaryota
Bacterial Infections
Animal Models
Protein-Serine-Threonine Kinases
3. Good health
Cell biology
Intestines
Nucleic acids
Insects
Pectobacterium carotovorum
Genetic interference
Experimental Organism Systems
Cell Processes
Cytokines
Drosophila
Female
Epigenetics
Anatomy
Signal Transduction
Research Article
Proto-oncogene tyrosine-protein kinase Src
lcsh:QH426-470
Arthropoda
MAP Kinase Signaling System
Immunology
Protein Serine-Threonine Kinases
Biology
Research and Analysis Methods
03 medical and health sciences
Model Organisms
Gene Types
Pseudomonas
Animals
Gene Regulation
Enhancer
Molecular Biology
Transcription factor
Ecology, Evolution, Behavior and Systematics
Cell Proliferation
Organisms
Biology and Life Sciences
Cell Biology
Transforming growth factor beta
Molecular Development
Invertebrates
Gastrointestinal Tract
lcsh:Genetics
Enterocytes
030104 developmental biology
Gene Expression Regulation
Immune System
biology.protein
RNA
Regulator Genes
Digestive System
Transcription Factors
Developmental Biology
Subjects
Details
- ISSN :
- 15537404 and 15537390
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- PLOS Genetics
- Accession number :
- edsair.doi.dedup.....4ea203ee1107fa9df9fb0e531df50cdb