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CtBP represses Dpp-dependent Mad activation during Drosophila eye development(Article)
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- ai3S –Instituto de Investigação e Inovação em Saúde, Porto, Portugal
- bIBMC– Instituto de Biologia Molecular e Celular, Porto, Portugal
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Abstract
Complex networks of signaling pathways maintain the correct balance between positive and negative growth signals, ensuring that tissues achieve proper sizes and differentiation pattern during development. In Drosophila, Dpp, a member of the TGFβ family, plays two main roles during larval eye development. In the early eye primordium, Dpp promotes growth and cell survival, but later on, it switches its function to induce a developmentally-regulated cell cycle arrest in the G1 phase and neuronal photoreceptor differentiation. To advance in the identification and characterization of regulators and targets of Dpp signaling required for retinal development, we carried out an in vivo eye-targeted double-RNAi screen to identify punt (Type II TGFβ receptor) interactors. Using a set of 251 genes associated with eye development, we identified CtBP, Dad, Ago and Brk as punt genetic interactors. Here, we show that downregulation of Ago, or conditions causing increased tissue growth including overexpression of Myc or CyclinD-Cdk4 are sufficient to partially rescue punt-dependent growth and photoreceptor differentiation. Interestingly, we show a novel role for the transcriptional co-repressor CtBP in inhibiting Dpp-dependent Mad activation by phosphorylation, downstream or in parallel to Dad, the inhibitory Smad. Furthermore, CtBP downregulation activates JNK signaling pathway, implying a complex regulation of signaling pathways by CtBP during eye development. © 2018 Elsevier Inc.
Indexed keywords
| EMTREE drug terms: | CtBP proteindecapentaplegic proteinrepressor proteinSmad proteintransforming growth factor beta receptorunclassified drugactivin receptor 2alcohol dehydrogenaseC-terminal binding proteinCdk4 protein, Drosophilacyclin dependent kinase 4DNA binding proteindpp protein, DrosophilaDrosophila proteinMAD protein, Drosophilaput protein, Drosophilarepressor proteintranscription factortransforming growth factor beta |
|---|---|
| EMTREE medical terms: | adultAgo geneanimal tissueArticleBrk genecontrolled studyCtBP geneDad genedevelopmental genedown regulationDrosophilaeye developmentfemaleG1 phase cell cycle checkpointgene interactiongenetic associationimagoinsect geneticsmalenonhumanphotoreceptorprimordiumpriority journalprotein phosphorylationrepressor geneRNA interferencesignal transductionanimalcell differentiationDrosophila melanogasterembryologyeyegene expression regulationgeneticsmetabolismmorphogenesisorganogenesisphysiology |
| MeSH: | Activin Receptors, Type IIAlcohol OxidoreductasesAnimalsCell DifferentiationCyclin-Dependent Kinase 4DNA-Binding ProteinsDrosophila melanogasterDrosophila ProteinsEyeGene Expression Regulation, DevelopmentalMorphogenesisOrganogenesisRepressor ProteinsSignal TransductionTranscription FactorsTransforming Growth Factor beta |
Chemicals and CAS Registry Numbers:
Smad protein, 62395-38-4; alcohol dehydrogenase, 9031-72-5; cyclin dependent kinase 4, 147014-97-9;
Activin Receptors, Type II; Alcohol Oxidoreductases; C-terminal binding protein; Cdk4 protein, Drosophila; Cyclin-Dependent Kinase 4; DNA-Binding Proteins; dpp protein, Drosophila; Drosophila Proteins; MAD protein, Drosophila; put protein, Drosophila; Repressor Proteins; Transcription Factors; Transforming Growth Factor beta
Funding details
| Funding sponsor | Funding number | Acronym |
|---|---|---|
| Fundação para a Ciência e a Tecnologia See opportunities | SFRH/BPD/95336/2013 | |
| Fundação para a Ciência e a Tecnologia See opportunities | SFRH/BD/95087/2013 | |
| European Regional Development Fund | ||
| NORTE 2020 |
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1
We thank David Arnosti, Iswar Hariharan, the Bloomington Drosophila Stock Center, the Vienna Drosophila RNAi Center, the Undergraduate Research Consortium in Functional Genomics, the Drosophila Genetic Resource Center, and the Developmental Studies Hybridoma Bank for reagents; Paula Sampaio (ALMF, IBMC) for technical support. We also thank Eva Carvalho and Rita Pinto for excellent technical assistance during this study. This work is a result of the project Norte-01–0145-FEDER-000008 - Porto Neurosciences and Neurologic Disease Research Initiative at I3S and the project Norte-01–0145-FEDER-000029 - Advancing Cancer Research: From basic knowledge to application, both supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) . NE is supported by doctoral grant from FCT ( SFRH/BD/95087/2013 ). LT is funded by a Fundação para a Ciência e Tecnologia Fellowship ( SFRH/BPD/95336/2013 ). PSP is a recipient of a Portuguese "Investigator FCT" contract. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Appendix A
- ISSN: 00121606
- CODEN: DEBIA
- Source Type: Journal
- Original language: English
- DOI: 10.1016/j.ydbio.2018.07.018
- PubMed ID: 30031756
- Document Type: Article
- Publisher: Elsevier Inc.
Pereira, P.S.; i3S –Instituto de Investigação e Inovação em Saúde, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.
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