Genetic control of programmed cell death in Drosophila (original) (raw)

Regulation of apoptosis in Drosophila

Cell Death and Differentiation, 2008

Insects have made major contributions to understanding the regulation of cell death, dating back to the pioneering work of Lockshin and Williams on death of muscle cells during postembryonic development of Manduca. A physically smaller cousin of moths, the fruit fly Drosophila melanogaster, offers unique advantages for studying the regulation of cell death in response to different apoptotic stimuli in situ. Different signaling pathways converge in Drosophila to activate a common death program through transcriptional activation of reaper, hid and grim. Reaper-family proteins induce apoptosis by binding to and antagonizing inhibitor of apoptosis proteins (IAPs), which in turn inhibit caspases. This switch from life to death relies extensively on targeted degradation of cell death proteins by the ubiquitin-proteasome pathway. Drosophila IAP-1 (Diap1) functions as an E3-ubiquitin ligase to protect cells from unwanted death by promoting the degradation of the initiator caspase Dronc. However, in response to apoptotic signals, Reaper-family proteins are produced, which promote the auto-ubiquitination and degradation of Diap1, thereby removing the 'brakes on death' in cells that are doomed to die. More recently, several other ubiquitin pathway proteins were found to play important roles for caspase regulation, indicating that the control of cell survival and death relies extensively on targeted degradation by the ubiquitin-proteasome pathway.

The head involution defective gene of Drosophila melanogaster functions in programmed cell death

Genes & Development, 1995

Access the most recent version at doi: 1995 9: 1694-1708 Genes Dev. M E Grether, J M Abrams, J Agapite, et al. functions in programmed cell death. The head involution defective gene of Drosophila melanogaster References http://genesdev.cshlp.org/content/9/14/1694#related-urls Article cited in: http://genesdev.cshlp.org/content/9/14/1694.refs.html Deletions of chromosomal region, 75C1,2 block virtually all programmed cell death (PCD) in the Drosophila embryo. We have identified a gene previously in this interval, reaper {rpr), which encodes an important regulator of PCD. Here we report the isolation of a second gene in this region, head involution defective (hid}, which plays a similar role in PCD. hid mutant embryos have decreased levels of cell death and contain extra cells in the head. We have cloned the hid gene and find that its expression is sufficient to induce PCD in cell death defective mutants. The hid gene appears to encode a novel 410-amino-acid protein, and its mRNA is expressed in regions of the embryo where cell death occurs. Ectopic expression of hid in the Drosophila retina results in eye ablation. This phenotype can be suppressed completely by expression of the anti-apoptotic p35 protein from baculovirus, indicating that p35 may act genetically downstream from hid. Cell deaths that occur during the development of essentially all metazoan animals display a characteristic ultrastructural morphology known as apoptosis [Kerr et al. WyUie et al. 1980). Because it is thought that these natural cell deaths result from the execution of an active, gene-directed cell suicide program, the process of apoptosis is also referred to as programmed cell death (PCD). Strong support for this concept has come from genetic studies in the nematode Caenorhabditis elegans, where a large number of mutations affecting specific aspects of PCD have been isolated and ordered into a genetic pathway [for review, see Hengartner and Horvitz 1994a, b). In particular, three genes, ced-3, ced-4, and ced-9, have been shown to control the onset of all somatic PCDs in the nematode. Interestingly, two of these genes, ced-3 and ced-9, have mammalian homologs that are believed to play a similar function during apoptosis. The ced-3 gene is homologous to a family of cysteine proteases that includes interleukin-l[3 converting enzyme, and ced-9 is a member of the bcl-2 family . Moreover, expression of human Bcl-2 can suppress some PCD in C. elegans and can partially Present addresses: ~University

Death to flies: Drosophila as a model system to study programmed cell death

Journal of Immunological Methods, 2002

Programmed cell death (PCD) is essential for the removal of unwanted cells and is critical for both restricting cell numbers and for tissue patterning during development. Components of the cell death machinery are remarkably conserved through evolution, from worms to mammals. Central to the PCD process is the family of cysteine proteases, known as caspases, which are activated by death-inducing signals. Comparisons between C. elegans and mammalian PCD have shown that there is additional complexity in the regulation of PCD in mammals. The fruitfly, Drosophila melanogaster, is proving an ideal genetically tractable model organism, of intermediary complexity between C. elegans and mammals, in which to study the intricacies of PCD. Here, we review the literature on PCD during Drosophila development, highlighting the methods used in these studies. D 2002 Published by Elsevier Science B.V.

Developmentally programmed cell death in Drosophila

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013

During the development of metazoans, programmed cell death (PCD) is essential for tissue patterning, removal of unwanted cells and maintaining homeostasis. In the past 20 years Drosophila melanogaster has been one of the systems of choice for studies involving developmental cell death, providing an ideal genetically tractable model of intermediary complexity between Caenorhabditis elegans and mammals. The lessons learned from studies using Drosophila indicate both the conserved nature of the many cell death pathways as well as novel and unexpected mechanisms. In this article we review the understanding of PCD during Drosophila development, highlighting the key mechanisms that are evolutionarily conserved as well as apparently unusual pathways, which indicate divergence, but provide evidence of complexity acquired during organismic evolution. This article is part of a Special Section entitled: Cell Death Pathways.

Apoptosis in Drosophila: compensatory proliferation and undead cells

The International Journal of Developmental Biology, 2009

Apoptosis (programmed cell death) is a conserved process in all animals, used to eliminate damaged or unwanted cells after stress events or during normal development to sculpt larval or adult structures. In Drosophila, it is known that stress events such as irradiation or heat shock give rise to high apoptotic levels which remove more than 50% of cells in imaginal discs. However, the surviving cells are able to restore normal size and pattern, indicating that they undergo additional proliferation. This "compensatory proliferation" is still poorly understood. One widely used method to study the properties of apoptotic cells is to keep them alive by expressing in them the baculoviral protein P35, which blocks the activity of the effector caspases. These "undead" cells acquire special features, such as the emission of the growth signals Dpp and Wg, changes in cellular morphology and induction of proliferation in neighbouring cells. Here, we review the various methods used in Drosophila to block apoptosis and its consequences, and focus on the generation and properties of undead cells in the wing imaginal disc. We describe their effects in epithelial architecture and growth in some detail, and discuss the possible relationship between undead cells and compensatory proliferation.

Apoptosis: the fly point of view

It is now established that genes involved in the execution of programmed cell death by apoptosis are relatively well conserved throughout evolution. However, the control of commitment to apoptosis exhibits some differences between organisms. In C. elegans, genetic studies have led to the identification of the ced genes (cell death) ced-3 and ced-4 that are essential to trigger cell death, and ced-9 that antagonizes the activities of ced-3 and ced-4. CED-3 is a caspase (cysteinyl aspartase) and CED-9 is homologous to proteins of the Bcl 2 family. In mammals, two main pathways of apoptosis have been identified. The intrinsic pathway is regulated by the bcl 2 family genes (the homologs of CED 9) but is more complex than in C. elegans and most data suggest that this family controls caspase activation by regulating mitochondrial membrane permeability and the release in the cytoplasm of proapoptotic factors including cytochrome c, which participate in caspases activation. An extrinsic pat...

Programmed death during Drosophila embryogenesis

Development

changes responsible for the selective affinity to these dyes. Cell death begins at stage 11 (~7 hours) of embryogenesis and thereafter becomes widespread, affecting many different tissues and regions of the embryo. Although the distribution of dying cells changes drastically over time, the overall pattern of cell death is highly reproducible for any given developmental stage. Detailed analysis of cell death in the central nervous system of stage 16 embryos (13-16 hours) revealed asymmetries in the exact number and position of dying cells on either side of the midline, suggesting that the decision to die may not be strictly predetermined at this stage. This work provides the basis for further molecular genetic studies on the control and execution of programmed cell death in Drosophila.

Apoptosis in Drosophila: which role for mitochondria?

Apoptosis, 2015

It is now well established that the mitochondrion is a central regulator of mammalian cell apoptosis. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, mainly because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and cell death in Drosophila occurs at the mitochondrial level. Numerous proteins, including RHG proteins and proteins of the Bcl-2 family that are key regulators of Drosophila apoptosis, constitutively or transiently localize in mitochondria. These proteins participate in the cell death process at different levels such as degradation of Diap1, a Drosophila IAP, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. Here, we review these mitochondrial events that might have their counterpart in human. Keywords Apoptosis Á Drosophila Á Mitochondria Á Bcl-2 family proteins Á RHG proteins Á IAP Á Mitochondrial dynamics Á Reactive oxygen species