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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., Author Summary Regenerative biology pursues to unveil the genetic networks triggered by tissue damage. Regeneration can occur after damage by cell death or by injury. We used the imaginal disc of Drosophila in which we genetically activated apoptosis or physically removed some parts and monitored the capacity to repair the damage. We found that dying cells generate a burst of reactive oxygen species (ROS) necessary to activate JNK and p38 signaling pathways in the surrounding living cells. The action of these pathways is necessary for the activation of the cytokines Unpaired (Upd). Eventually, Upd will turn on the JAK/STAT signaling pathway to induce regenerative growth. Thus, we present here a module of signals that depends on oxidative stress and that, through the p38-JNK interplay, will activate cytokine-dependent regeneration.

A study in the Drosophila wing suggests a crucial role of p53 in the coordination of growth between adjacent cell populations to maintain organ proportions and shape., Coordination of growth between and within organs contributes to the generation of well-proportioned organs and functionally integrated adults. The mechanisms that help to coordinate the growth between different organs start to be unravelled. However, whether an organ is able to respond in a coordinated manner to local variations in growth caused by developmental or environmental stress and the nature of the underlying molecular mechanisms that contribute to generating well-proportioned adult organs under these circumstances remain largely unknown. By reducing the growth rates of defined territories in the developing wing primordium of Drosophila, we present evidence that the tissue responds as a whole and the adjacent cell populations decrease their growth and proliferation rates. This non-autonomous response occurs independently of where growth is affected, and it is functional all throughout development and contributes to generate well-proportioned adult structures. Strikingly, we underscore a central role of Drosophila p53 (dp53) and the apoptotic machinery in these processes. While activation of dp53 in the growth-depleted territory mediates the non-autonomous regulation of growth and proliferation rates, effector caspases have a unique role, downstream of dp53, in reducing proliferation rates in adjacent cell populations. These new findings indicate the existence of a stress response mechanism involved in the coordination of tissue growth between adjacent cell populations and that tissue size and cell cycle proliferation can be uncoupled and are independently and non-autonomously regulated by dp53., Author Summary The coordination of growth within and between organs contributes to the generation of functionally integrated structures and well-proportioned animals and plants. Though these issues have fascinated biologists for centuries, the responsible molecular mechanisms remain largely uncharacterized. In this work, we have used the Drosophila wing primordium to show that adjacent cell populations grow and proliferate in a coordinated manner. By reducing growth rates in specific territories within the developing wing, we showed that the tissue responds as a whole and that in adjacent cell populations the growth and cell cycle rates are concomitantly reduced, thus maintaining tissue proportions and normal wing shape. Interestingly, we show that the Drosophila tumour suppressor protein dp53 and apoptotic machinery play a key role in coordinating this tissue-wide response. Both growth and proliferation rates are regulated in a coordinated and non-autonomous manner by the activity of dp53, whilst the apoptotic pathway has a specific and non-autonomous role in regulating cell proliferation rates. Our studies describe a novel mechanism for regulating tissue growth in developing organs that may ultimately be relevant for other processes involving coordination of growth, such as tissue renewal, regeneration, and cancer.