Regulation of UV-Induced Apoptosis

Buck Institute For Research On Aging, Novato CA

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Abstract

DESCRIPTION (provided by applicant): Tissue homeostasis in the retina depends on maintaining a precise balance between survival and apoptosis of damaged cells. Signaling mechanisms that control cellular responses to light and UV-induced DNA damage thus play critical roles in preserving retinal function. The Jasper lab has characterized such signaling mechanisms using the developing Drosophila retina as a genetically accessible model system to study the regulation of UV-induced cell death of photoreceptors. In the course of these studies, it has been established that retinal homeostasis is not only maintained by cell autonomous mechanisms, but also by systemic signals. In preliminary data presented here, it was further found that retina-associated blood cells (hemocytes) also play a critical role in promoting tissue homeostasis. In mammals, tissue-resident macrophages (or microglia) play an important role in promoting homeostasis of the retina, influencing retinal diseases, including age-related macular degeneration. The signaling mechanisms that govern the interaction between neurons and macrophages, however, are only beginning to be understood, and appropriate genetic model systems to explore these mechanisms remain elusive. This proposal introduces the Drosophila retina as an accessible model to study this interaction in detail. The specific preliminary results on which the proposal is based identify the transcription factor Schnurri as a critical regulator of tissue homeostasis in the retina by regulating hemocyte function. Schnurri acts in the retina to promote the expression of cytokines of the PDGF and TNF family that activate retina-associated hemocytes. This activation event, in turn, is required to promote phagocytic activity of hemocytes and is critical for the preservation of retinal homeostasis in the event of a genotoxic challenge. The proposal intends to further characterize and clarify this model, by (i) characterizing signaling events in photoreceptors that control the cytokine response to DNA damage, (ii) exploring the signaling pathways regulating hemocyte activation, and (iii) testing the hypothesis that phagocytic activity of hemocytes is critical to prevent excessive death in the challenged retina. Important technical advantages of the Drosophila system for the study of hemocyte / retina interactions include the ability to perturb gene function with spatiotemporal precision and to characterize resulting phenotypes rapidly and quantitatively. It is thus anticipated that significant progress can be made in our understanding of fundamental signaling mechanisms regulating the interaction between retinal cells and resident macrophages and of the consequences of this interaction for tissue health. Since the analyzed cellular and molecular signaling mechanisms are widely conserved, it can be anticipated that significant insight can be obtained that will be of relevance to our understanding of the control of retinal homeostasis in humans.