Ask1 and Akt act synergistically to promote ROS-dependent regeneration in Drosophila.

Paula Santabárbara-Ruiz,Florenci Serras,Marco Milán,Giacomo Viola,Lidia Pérez,José Esteban-Collado,Josep F Abril,Montserrat Corominas,Gregory P Copenhaver

doi:10.1371/journal.pgen.1007926

Abstract

How cells communicate to initiate a regenerative response after damage has captivated scientists during the last few decades. It is known that one of the main signals emanating from injured cells is the Reactive Oxygen Species (ROS), which propagate to the surrounding tissue to trigger the replacement of the missing cells. However, the link between ROS production and the activation of regenerative signaling pathways is not yet fully understood. We describe here the non-autonomous ROS sensing mechanism by which living cells launch their regenerative program. To this aim, we used Drosophila imaginal discs as a model system due to its well-characterized regenerative ability after injury or cell death. We genetically-induced cell death and found that the Apoptosis signal-regulating kinase 1 (Ask1) is essential for regenerative growth. Ask1 senses ROS both in dying and living cells, but its activation is selectively attenuated in living cells by Akt1, the core kinase component of the insulin/insulin-like growth factor pathway. Akt1 phosphorylates Ask1 in a secondary site outside the kinase domain, which attenuates its activity. This modulation of Ask1 activity results in moderate levels of JNK signaling in the living tissue, as well as in activation of p38 signaling, both pathways required to turn on the regenerative response. Our findings demonstrate a non-autonomous activation of a ROS sensing mechanism by Ask1 and Akt1 to replace the missing tissue after damage. Collectively, these results provide the basis for understanding the molecular mechanism of communication between dying and living cells that triggers regeneration.

Highlights

Organisms are continuously exposed to a wide variety of environmental stressors that can cause deterioration and cell death
One of the early events that occur after tissue damage consists on the production of Reactive Oxygen Species (ROS), that signal to the surrounding tissue to initiate wound healing and regeneration
We found that the Drosophila Apoptosis signal-regulating kinase 1 (Ask1), a protein that is sensitive to oxidative stress, is a key player in this scenario

Summary

Introduction

Organisms are continuously exposed to a wide variety of environmental stressors that can cause deterioration and cell death. Tissues overcome the effect of those stressors by replacing damaged cells to restore homeostasis. Understanding the early signals that initiate the response to damage is an essential issue in regenerative medicine. Regeneration can be monitored in Drosophila imaginal discs, which are well-characterized epithelial sacs capable to regenerate after genetically-induced apoptosis or when parts are physically removed (reviewed in [1]). Compiling evidence supports that reactive oxygen species (ROS) fuel wound healing and oxygen-dependent redox-sensitive signaling processes involved in damage response [2,3,4]. Genetically-induced apoptosis in the imaginal discs, using the Gal4/UAS system, leads to the production of ROS which propagate to the surrounding neighbors [5,6,7]. Oxidative stress has been associated with several pathologies, it has been described that low levels of ROS can be beneficial for signal transduction [8]

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Results

Conclusion