ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration.
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.
Departament de Genètica, Facultat de Biologia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
Paula
P
Santabárbara-Ruiz
Departament de Genètica, Facultat de Biologia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
Mireya
M
López-Santillán
Departament de Genètica, Facultat de Biologia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
Irene
I
Martínez-Rodríguez
Departament de Genètica, Facultat de Biologia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
Anahí
A
Binagui-Casas
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
Lídia
L
Pérez
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; ICREA, Catalan Institution for Research and Advanced Studies, Barcelona, Spain.
Marco
M
Milán
Departament de Genètica, Facultat de Biologia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
Montserrat
M
Corominas
Departament de Genètica, Facultat de Biologia and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
Florenci
F
Serras
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D060227:Imaginal Discs / Q000254:growth & development; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014921:Wings, Animal / Q000254:growth & development; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*
D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C115570:upd1 protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases