title: EGFR/Ras Signaling Controls Drosophila Intestinal Stem Cell Proliferation via Capicua-Regulated Genes.
abstract: Epithelial renewal in the Drosophila intestine is orchestrated by Intestinal Stem Cells (ISCs). Following damage or stress the intestinal epithelium produces ligands that activate the epidermal growth factor receptor (EGFR) in ISCs. This promotes their growth and division and, thereby, epithelial regeneration. Here we demonstrate that the HMG-box transcriptional repressor, Capicua (Cic), mediates these functions of EGFR signaling. Depleting Cic in ISCs activated them for division, whereas overexpressed Cic inhibited ISC proliferation and midgut regeneration. Epistasis tests showed that Cic acted as an essential downstream effector of EGFR/Ras signaling, and immunofluorescence showed that Cic's nuclear localization was regulated by EGFR signaling. ISC-specific mRNA expression profiling and DNA binding mapping using DamID indicated that Cic represses cell proliferation via direct targets including string (Cdc25), Cyclin E, and the ETS domain transcription factors Ets21C and Pointed (pnt). pnt was required for ISC over-proliferation following Cic depletion, and ectopic pnt restored ISC proliferation even in the presence of overexpressed dominant-active Cic. These studies identify Cic, Pnt, and Ets21C as critical downstream effectors of EGFR signaling in Drosophila ISCs.
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) - Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) Allianz, Heidelberg, Germany.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Biochemie-Zentrum der Universität Heidelberg (BZH), Heidelberg, Germany.
authors.forename: Nati
authors.initials: N
authors.lastname: Ha
authors.affiliation: Institut de Biologia Molecular de Barcelona-CSIC, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Forés
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) - Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) Allianz, Heidelberg, Germany.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) - Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) Allianz, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Gläßer
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) - Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) Allianz, Heidelberg, Germany.
authors.forename: Julieta
authors.initials: J
authors.lastname: Maldera
authors.affiliation: Institut de Biologia Molecular de Barcelona-CSIC, Parc Científic de Barcelona, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Jiménez
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ) - Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) Allianz, Heidelberg, Germany.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000096:biosynthesis / Q000235:genetics*; D007422:Intestines / Q000166:cytology / Q000254:growth & development; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D018010:Receptors, Invertebrate Peptide / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C000608103:Ets21C protein, Drosophila; D024002:HMGB Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D018010:Receptors, Invertebrate Peptide; D012097:Repressor Proteins; D014157:Transcription Factors; C404284:cic protein, Drosophila; C083884:pnt protein, Drosophila; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors