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      Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

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          Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions.


          eLife digest

          The tissues of developing organisms can be shaped by apoptosis, a form of regulated cell killing. Although this process can occur in individual cells, apoptotic signals may also dictate the ‘communal death’ of many cells simultaneously. This occurs frequently in animal development: in human fetuses, for example, cells in the hand are directed to die to remove webbing between the fingers.

          Apoptosis has been thought to resemble a form of silent suicide by cells, but more recent work suggests that apoptotic cells can also transmit signals. Now, Pérez-Garijo et al. find that these cells can stimulate other cells to die in both fruit flies and mice.

          In fruit flies, apoptosis is activated by proteins known as Grim, Hid and Reaper. To explore whether apoptotic cells could communicate with other cells, Pérez-Garijo et al. created ‘undead’ cells in which one of these proteins was turned on, but other downstream proteins (that are responsible for the cellular execution phase of apoptosis) had been turned off: these cells were undergoing apoptosis, but could not complete the process and die.

          Strikingly, undead cells in the posterior (back) region of the wing imaginal disc—the tissue in the larva that gives rise to the wing in the adult fruit fly—could trigger apoptosis in cells in the anterior (front) half. Pérez-Garijo et al. found that the JNK pathway activated apoptosis in anterior cells. In fruit flies, the Eiger protein turns on this pathway; when Eiger was absent from posterior cells in the wing imaginal disc, apoptosis in anterior cells ceased, indicating that Eiger might signal at long range.

          Eiger is related to a protein called TNF that has been implicated in cycles of destruction and renewal of hair follicles in mice. Pérez-Garijo et al. found that TNF is produced by apoptotic cells in hair follicles, and that blocking TNF inhibits the death of other cells in the same cohort: this suggests that a common mechanism could regulate the communal death of cells in flies and mammals. These studies therefore shed light on a conserved pathway in the modulation of tissue development.


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          Most cited references 77

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          Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.

           N Perrimon,  H. Brand (1993)
          We have designed a system for targeted gene expression that allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns. The gene encoding the yeast transcriptional activator GAL4 is inserted randomly into the Drosophila genome to drive GAL4 expression from one of a diverse array of genomic enhancers. It is then possible to introduce a gene containing GAL4 binding sites within its promoter, to activate it in those cells where GAL4 is expressed, and to observe the effect of this directed misexpression on development. We have used GAL4-directed transcription to expand the domain of embryonic expression of the homeobox protein even-skipped. We show that even-skipped represses wingless and transforms cells that would normally secrete naked cuticle into denticle secreting cells. The GAL4 system can thus be used to study regulatory interactions during embryonic development. In adults, targeted expression can be used to generate dominant phenotypes for use in genetic screens. We have directed expression of an activated form of the Dras2 protein, resulting in dominant eye and wing defects that can be used in screens to identify other members of the Dras2 signal transduction pathway.
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            Apoptosis in the pathogenesis and treatment of disease.

            In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.
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              Regulation of wound healing by growth factors and cytokines.

              Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process.

                Author and article information

                Role: Reviewing editor
                eLife Sciences Publications, Ltd
                24 September 2013
                : 2
                [1 ]Strang Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute, The Rockefeller University , New York, United States
                New York University School of Medicine , United States
                New York University School of Medicine , United States
                Author notes
                [* ]For correspondence: steller@
                Copyright © 2013, Pérez-Garijo et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Funded by: Howard Hughes Medical Institute
                Award Recipient :
                Funded by: National Institutes of Health
                Award ID: R01-AR050452
                Award Recipient :
                Funded by: Fundacion Ramon Areces
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Research Article
                Developmental Biology and Stem Cells
                Custom metadata
                A common mechanism might regulate the communal death of cells in flies and mammals.


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