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  • Review Article
  • Published:

The genetics of cell death: approaches, insights and opportunities in Drosophila

Nature Reviews Genetics volume 5, pages 911–922 (2004)Cite this article

Key Points

  • Programmed cell death, or apoptosis, is ubiquitous in animals, where it has an important function in development and homeostasis.

  • Drosophila melanogaster is an attractive system in which to study apoptosis because it occurs throughout the fly life cycle and in response to a number of insults that are relevant to human disease. In addition, where studied, cell death in flies and mammals involves similar machinery and mechanisms of regulation.

  • Caspases are the core of the cell-death machinery, and much of the regulation of cell death revolves around controlling their activation and their activity once they are activated. Inhibition of DIAP1, an anti-apoptotic IAP family member essential for cell survival, is an important site of pro-apoptotic protein action in D. melanogaster.

  • Several outstanding questions remain in the study of cell death in D. melanogaster. For example, how do the known components of the canonical cell-death pathway interact and regulate each other's activities? How many core components remain to be discovered? And which other non-canonical cell-death pathways are involved? These, and other issues can be studied using the wide range of sophisticated genetic and molecular techniques that have become available for this organism.

  • F2 loss-of-function screens have led to the identification of important cell-death regulators. New tools have increased the power of these screens to rapidly identify interesting genes.

  • Clone-based screens that involve tissue-specific loss-of-function provide an approach to identifying cell-death regulators in any tissue and at any life stage.

  • The dominant modifier screen provides a method for rapidly identifying components of a specific death-signalling pathway. These are identified as enhancers or suppressors of a dominant phenotype that has been created to produce a sensitized genetic background.

  • Cell-culture-based RNAi screens can identify genes that are required for cell survival or cell death in different contexts.

Abstract

Cell death is ubiquitous in metazoans and involves the action of an evolutionarily conserved process known as programmed cell death or apoptosis. In Drosophila melanogaster, it is now uniquely possible to screen for genes that determine the fate — life or death — of any cell or population of cells during development and in the adult. This review describes these genetic approaches and the key insights into cell-death mechanisms that have been obtained, as well as the outstanding questions that these techniques can help to answer.

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Figure 1: The core apoptosis machine compared in Caenorhabditis elegans, Drosophila melanogaster and mammals.
Figure 2: Regulation of cell death in Drosophila melanogaster.
Figure 3: Non-apoptotic roles of apoptotic caspases in Drosophila melanogaster.
Figure 4: Genetic screens for cell-death regulators in Drosophila melanogaster.
Figure 5: Cell death phenotypes in Drosophila melanogaster.

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Acknowledgements

Work in the authors' laboratories is supprted by NIH (National Institutes of Health) grants. We apologize to authors whose work could not be cited directly owing to space limitations.

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Authors and Affiliations

  1. Division of Biology, MC156-29, California Institute of Technology, 1200 East California Boulevard, Pasadena, 91125, California, USA

    Bruce A. Hay & Jun R. Huh

  2. Department of Neurology, Brain Research Institute, The David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Ming Guo

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  1. Bruce A. Hay
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Correspondence to Bruce A. Hay.

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DATABASES

Entrez

rpr

hid

grim

skl

hippo

salvador

warts

OMIM

Parkinson disease

Swiss-Prot

CED-3

CED-4

CED-9

DRONC

DIAP1

FURTHER INFORMATION

Guo's laboratory

Hay's laboratory

Glossary

RNAi-MEDIATED KNOCKDOWN

A phenomenon in which the expression of a gene is temporarily inhibited ('knocked down') when a complementary dsRNA molecule is introduced into the organism.

SATURATION

A screen that is designed to induce at least one mutation in every gene is said to have been carried out to saturation.

BACULOVIRUS CASPASE INHIBITOR P35

Baculoviruses are large DNA viruses that infect arthropods. p35 is a baculovirus-encoded protein that inhibits cell death by acting as a suicide substrate for many caspases.

RNA INTERFERENCE (RNAi)

A form of post-transcriptional gene silencing, in which dsRNA induces degradation of the homologous endogenous transcripts, mimicking the effect of the reduction, or loss, of gene activity.

EPISTASIS

When the phenotype associated with mutation of a gene (A) is masked by mutation in a second gene (B), B is said to be epistatic to A. In a switch pathway (a pathway in which the output is one of two states, often developmental fates), such an observation would indicate that genes A and B act in the same pathway, and that A acts through B.

SENSITIZED GENETIC BACKGROUND

A genetic background in which modest (twofold) changes in the dose of pathway components produce a phenotype that would not be observed in a wild-type background.

DOMINANT MODIFIER SCREEN

A signalling pathway is hyperactivated or partially deactivated in a specific tissue. These flies are often sensitive to modest changes in the levels of pathway components (heterozygosity) that would otherwise not result in a visible phenotype — but only in the specific tissue that is targeted.

NURSE CELLS

Female germline-derived cells that support the development of the oocyte. Nurse cells are interconnected to each other and to the developing oocyte through intercellular bridges that facilitate transport of RNA and protein into the growing oocyte.

IMAGINAL DISC

An epithelial sheet of cells that occurs as a sac-like infolding of the epithelium in the larva. Small groups of imaginal disc founder cells arise in the embryo. They continue to divide until pupation, when they differentiate into many adult structures (wings, legs, eyes, antennae and genitalia).

SYNCYTIUM

A multinucleate cell in which the nuclei are not separated by cell membranes.

AUTOPHAGY

In autophagic cell death, as opposed to apoptotic cell death, the cell is degraded largely from within, with little or no help from phagocytes. Bulk cytoplasm and organelles are sequestered within double-membrane-bound vesicles. These ultimately fuse with the lysosome and their contents are degraded.

SPERMATID

A post-meiotic haploid male germ cell.

BORDER CELLS

A small group of specialized somatic follicle cells. They delaminate from the follicular epithelium, invade the underlying germline tissue and migrate towards the oocyte.

MITOTIC RECOMBINATION

A crossover between two homologous dsDNA molecules that leads to a physical exchange of DNA and genetic information. This recombination occurs frequently during meiosis, but is relatively rare during mitosis. As a consequence of mitotic recombination, cells can undergo a 'loss of heterozygosity' or gene conversion.

BALANCED STOCK

A stock that carries a lethal mutation on one chromosome homologue, and a balancer chromosome on the other. A balancer chromosome carries multiple inversions that prevent recombination with the lethal-bearing chromosome, a recessive lethal mutation and a dominant marker. Matings between balanced lethal flies produce only balanced lethal adult progeny — a stable stock.

ISOGENIC

Cells or organisms that are derived from the same parent and therefore have almost identical genomes.

GERMLINE CLONE SCREEN

A genetic screen in which clones of homozygous-mutant germline tissue are produced in adult females. Oocytes and eggs derived from these clones (which can be distinguished from those derived from heterozygous germline tissue in several ways) can be examined for phenotypes during oogenesis and embryogenesis.

P-ELEMENT

A member of a family of transposable elements that are widely used as the basis of tools for mutating and manipulating the genome of Drosophila melanogaster.

CELL MICROARRAYS

Cells are plated directly onto a slide containing thousands of microarrayed spots of DNA. Cells landing on these spots are transfected with the arrayed plasmids, and can then be scored in various assays.

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Hay, B., Huh, J. & Guo, M. The genetics of cell death: approaches, insights and opportunities in Drosophila. Nat Rev Genet 5, 911–922 (2004). https://doi.org/10.1038/nrg1491

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  • DOI: https://doi.org/10.1038/nrg1491

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