ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation During Drosophila Regeneration

PLoS Genet. 2015 Oct 23;11(10):e1005595. doi: 10.1371/journal.pgen.1005595. eCollection 2015 Oct.

Abstract

Upon apoptotic stimuli, epithelial cells compensate the gaps left by dead cells by activating proliferation. This has led to the proposal that dying cells signal to surrounding living cells to maintain homeostasis. Although the nature of these signals is not clear, reactive oxygen species (ROS) could act as a signaling mechanism as they can trigger pro-inflammatory responses to protect epithelia from environmental insults. Whether ROS emerge from dead cells and what is the genetic response triggered by ROS is pivotal to understand regeneration of Drosophila imaginal discs. We genetically induced cell death in wing imaginal discs, monitored the production of ROS and analyzed the signals required for repair. We found that cell death generates a burst of ROS that propagate to the nearby surviving cells. Propagated ROS activate p38 and induce tolerable levels of JNK. The activation of JNK and p38 results in the expression of the cytokines Unpaired (Upd), which triggers the JAK/STAT signaling pathway required for regeneration. Our findings demonstrate that this ROS/JNK/p38/Upd stress responsive module restores tissue homeostasis. This module is not only activated after cell death induction but also after physical damage and reveals one of the earliest responses for imaginal disc regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Proliferation / genetics
  • Drosophila Proteins / biosynthesis
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Gene Expression Regulation, Developmental
  • Imaginal Discs / growth & development
  • JNK Mitogen-Activated Protein Kinases / biosynthesis
  • JNK Mitogen-Activated Protein Kinases / genetics*
  • Reactive Oxygen Species / metabolism
  • Regeneration / genetics*
  • Signal Transduction
  • Stress, Physiological / genetics
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*
  • Wings, Animal / growth & development
  • p38 Mitogen-Activated Protein Kinases / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / genetics*

Substances

  • Drosophila Proteins
  • Reactive Oxygen Species
  • Transcription Factors
  • upd1 protein, Drosophila
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases

Grant support

This project was funded by grants BFU2009-09781, CSD2007-00008, and BFU2012-36888, Ministerio de Economía y Competitividad, Spain (http://www.mineco.gob.es/portal/site/mineco/) to the FS and MC labs and by grant BFU2010-21123, PCIN-2013-048 and CSD2007-00008 to the MM lab. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.