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Developmental cell biology

Developmental apoptosis in C. elegans: a complex CEDnario

Key Points

  • Apoptosis is an evolutionarily conserved programme that is important for the development and homeostasis of most multicellular animals. It contributes to the elimination of useless, damaged or harmful cells.

  • In Caenorhabditis elegans hermaphrodites, >10% of the somatic cells that are born undergo apoptosis ? these cells were healthy but unnecessary. Apoptosis also occurs normally in the C. elegans hermaphrodite germ line, where it claims 50% of the developing oocytes.

  • Genetic studies in C. elegans have led to the identification and functional characterization of conserved key components of the apoptotic cascade. This includes the pro-apoptotic proteins EGL-1 (a BH3-only-domain protein), CED-4 (an adaptor protein) and CED-3 (caspase), as well as the anti-apoptotic protein CED-9 (Bcl-2-like).

  • Crystallization of the EGL-1?CED-9 and CED-9?CED-4 complexes has provided a detailed mechanistic view of apoptosis activation in C. elegans. In living cells, CED-4 dimers are sequestered through interaction with one CED-9 molecule. In cells that are fated to die, EGL-1 binds to CED-9, which induces a conformational change in CED-9 that disrupts the interaction between CED-9 and the CED- 4 dimer. Once freed from CED-9, CED-4 dimers come together to form tetramers, which interact with and facilitate CED-3 autoactivation.

  • The regulation of developmental apoptosis is poorly understood molecularly, even in a simple metazoan like C. elegans. In this organism, experimental data support models in which pathways that control the transcriptional activation of egl-1 determine the fate of two neuronal cell types (the neurosecretory motor (NSM) sister cells and the hermaphrodite-specific neurons (HSNs)), as well as the fate of germ cells after DNA damage.

  • Many interesting questions remain to be elucidated in the study of developmental apoptosis in C. elegans. What is the role of the mitochondria in apoptotic cell death? How do engulfment and DNA degradation contribute to cell killing? What transcriptional networks control the expression of egl-1 in the other cell types that succumb to apoptosis? Powerful genetic screens, and emerging new genomics and proteomics tools, should allow the research community to answer these outstanding questions in the near future.

Abstract

Apoptosis, an evolutionarily conserved programme of cellular self-destruction, is essential for the development and survival of most multicellular animals. It is required to ensure functional organ architecture and to maintain tissue homeostasis. During development of the simple nematode Caenorhabditis elegans, apoptosis claims over 10% of the somatic cells that are generated ? these cells were healthy but unnecessary. Exciting insights into the regulation and execution of apoptosis in C. elegans have recently been made. These new findings will undoubtedly influence our perception of developmental apoptosis in more complex species, including humans.

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Figure 1: Developmental apoptosis in C. elegans.
Figure 2: The genetic pathway for programmed cell death in C. elegans.
Figure 3: Molecular model of apoptosis activation in C. elegans.
Figure 4: Transcriptional regulation of the pro-apoptotic gene egl-1.

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References

  1. Hipfner, D. R. & Cohen, S. M. Connecting proliferation and apoptosis in development and disease. Nature Rev. Mol. Cell Biol. 5, 805?815 (2004).

    Article  CAS  Google Scholar 

  2. Jacobson, M. D., Weil, M. & Raff, M. C. Programmed cell death in animal development. Cell 88, 347?354 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Vaux, D. L. & Korsmeyer, S. J. Cell death in development. Cell 96, 245?254 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Meier, P., Finch, A. & Evan, G. Apoptosis in development. Nature 407, 796?801 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Baehrecke, E. H. How death shapes life during development. Nature Rev. Mol. Cell Biol. 3, 779?787 (2002).

    Article  CAS  Google Scholar 

  6. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239?257 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wyllie, A. H., Kerr, J. F. & Currie, A. R. Cell death: the significance of apoptosis. Int. Rev. Cytol. 68, 251?306 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555?556 (1980).

    Article  CAS  PubMed  Google Scholar 

  9. Baehrecke, E. H. Autophagy: dual roles in life and death? Nature Rev. Mol. Cell Biol. 6, 505?510 (2005).

    Article  CAS  Google Scholar 

  10. Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817?829 (1986). This landmark paper describes the genetic regulation of apoptosis in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  11. Metzstein, M. M., Stanfield, G. M. & Horvitz, H. R. Genetics of programmed cell death in C. elegans: past, present and future. Trends Genet. 14, 410?416 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Grimsley, C. & Ravichandran, K. S. Cues for apoptotic cell engulfment: eat-me, don't eat-me and come-get-me signals. Trends Cell Biol. 13, 648?656 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Reddien, P. W. & Horvitz, H. R. The engulfment process of programmed cell death in Caenorhabditis elegans. Annu. Rev. Cell Dev. Biol. 20, 193?221 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Nagata, S. DNA degradation in development and programmed cell death. Annu. Rev. Immunol. 23, 853?875 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110?156 (1977).

    Article  CAS  PubMed  Google Scholar 

  16. Kimble, J. & Hirsh, D. The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. Dev. Biol. 70, 396?417 (1979).

    Article  CAS  PubMed  Google Scholar 

  17. Sulston, J. E., Schierenberg, E., White, J. G. & Thomson, J. N. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64?119 (1983).

    Article  CAS  PubMed  Google Scholar 

  18. Hedgecock, E. M., Sulston, J. E. & Thomson, J. N. Mutations affecting programmed cell deaths in the nematode Caenorhabditis elegans. Science 220, 1277?1279 (1983).

    Article  CAS  PubMed  Google Scholar 

  19. Gumienny, T. L., Lambie, E., Hartwieg, E., Horvitz, H. R. & Hengartner, M. O. Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126, 1011?1022 (1999).

    CAS  PubMed  Google Scholar 

  20. Desai, C., Garriga, G., McIntire, S. L. & Horvitz, H. R. A genetic pathway for the development of the Caenorhabditis elegans HSN motor neurons. Nature 336, 638?646 (1988).

    Article  CAS  PubMed  Google Scholar 

  21. Ellis, R. E., Jacobson, D. M. & Horvitz, H. R. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129, 79?94 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hengartner, M. O., Ellis, R. E. & Horvitz, H. R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494?499 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198?202 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Hoeppner, D. J., Hengartner, M. O. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202?206 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Parrish, J. et al. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 412, 90?94 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Wang, X., Yang, C., Chai, J., Shi, Y. & Xue, D. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298, 1587?1592 (2002). References 23?26 present interesting evidence that engulfment or DNA degradation of apoptotic cells also contribute to cell killing.

    Article  CAS  PubMed  Google Scholar 

  27. Shaham, S. & Horvitz, H. R. Developing Caenorhabditis elegans neurons may contain both cell-death protective and killer activities. Genes Dev. 10, 578?591 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β- converting enzyme. Cell 75, 641?652 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Xue, D. & Horvitz, H. R. Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein. Nature 377, 248?251 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Xue, D., Shaham, S. & Horvitz, H. R. The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev. 10, 1073?1083 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Riedl, S. J. & Shi, Y. Molecular mechanisms of caspase regulation during apoptosis. Nature Rev. Mol. Cell Biol. 5, 897?907 (2004).

    Article  CAS  Google Scholar 

  32. Earnshaw, W. C., Martins, L. M. & Kaufmann, S. H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383?424 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Yuan, J. & Horvitz, H. R. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116, 309?320 (1992).

    CAS  PubMed  Google Scholar 

  34. Yang, X., Chang, H. Y. & Baltimore, D. Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Science 281, 1355?1357 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Rodriguez, J. & Lazebnik, Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 13, 3179?3184 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hengartner, M. O. & Horvitz, H. R. Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature 369, 318?320 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Hengartner, M. O. & Horvitz, H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665?676 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Conradt, B. & Horvitz, H. R. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93, 519?529 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Cory, S., Huang, D. C. & Adams, J. M. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22, 8590?8607 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell 116, 205?219 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Schumacher, B. et al. C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ. 12, 153?161 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. James, C., Gschmeissner, S., Fraser, A. & Evan, G. I. CED-4 induces chromatin condensation in Schizosaccharomyces pombe and is inhibited by direct physical association with CED-9. Curr. Biol. 7, 246?252 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Spector, M. S., Desnoyers, S., Hoeppner, D. J. & Hengartner, M. O. Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature 385, 653?656 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Wu, D., Wallen, H. D. & Nunez, G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 275, 1126?1129 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Wu, D., Wallen, H. D., Inohara, N. & Nunez, G. Interaction and regulation of the Caenorhabditis elegans death protease CED-3 by CED-4 and CED-9. J. Biol. Chem. 272, 21449?21454 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. del Peso, L., Gonzalez, V. M. & Nunez, G. Caenorhabditis elegans EGL-1 disrupts the interaction of CED-9 with CED-4 and promotes CED-3 activation. J. Biol. Chem. 273, 33495?33500 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. del Peso, L., Gonzalez, V. M., Inohara, N., Ellis, R. E. & Nunez, G. Disruption of the CED-9?CED-4 complex by EGL-1 is a critical step for programmed cell death in Caenorhabditis elegans. J. Biol. Chem. 275, 27205?27211 (2000).

    CAS  PubMed  Google Scholar 

  48. Chen, F. et al. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science 287, 1485?1489 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Seshagiri, S. & Miller, L. K. Caenorhabditis elegans CED-4 stimulates CED-3 processing and CED-3-induced apoptosis. Curr. Biol. 7, 455?460 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Yan, N. et al. Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol. Cell 15, 999?1006 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Parrish, J., Metters, H., Chen, L. & Xue, D. Demonstration of the in vivo interaction of key cell death regulators by structure-based design of second-site suppressors. Proc. Natl Acad. Sci. USA 97, 11916?11921 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yan, N. et al. Structure of the CED-4?CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 437, 831?837 (2005). References 50 and 52 provide a detailed molecular mechanism of apoptosis activation in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  53. Fairlie, W. D. et al. CED-4 forms a 2:2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13. Cell Death Differ. 16 Sept 2005 (10.1038/sj.cdd.4401762).

  54. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479?489 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Hu, Y., Ding, L., Spencer, D. M. & Nunez, G. WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation. J. Biol. Chem. 273, 33489?33494 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Srinivasula, S. M., Ahmad, M., Fernandes-Alnemri, T. & Alnemri, E. S. Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol. Cell 1, 949?957 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Parrish, J. Z. & Xue, D. Functional genomic analysis of apoptotic DNA degradation in C. elegans. Mol. Cell 11, 987?996 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Jagasia, R., Grote, P., Westermann, B. & Conradt, B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433, 754?760 (2005). Demonstrates, for the first time, a causal role for mitochondria in apoptotic cell death in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  59. Karbowski, M. & Youle, R. J. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ. 10, 870?880 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Youle, R. J. & Karbowski, M. Mitochondrial fission in apoptosis. Nature Rev. Mol. Cell Biol. 6, 657?663 (2005).

    Article  CAS  Google Scholar 

  61. Labrousse, A. M., Zappaterra, M. D., Rube, D. A. & van der Bliek, A. M. C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol. Cell 4, 815?826 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Vaux, D. L. & Silke, J. IAPs, RINGs and ubiquitylation. Nature Rev. Mol. Cell Biol. 6, 287?297 (2005).

    Article  CAS  Google Scholar 

  63. Hinds, M. G., Norton, R. S., Vaux, D. L. & Day, C. L. Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nature Struct. Biol. 6, 648?651 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Silke, J. & Vaux, D. L. Two kinds of BIR-containing protein ? inhibitors of apoptosis, or required for mitosis. J. Cell Sci. 114, 1821?1827 (2001).

    CAS  PubMed  Google Scholar 

  65. Wilson, R. et al. The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis. Nature Cell Biol. 4, 445?450 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Bergmann, A., Yang, A. Y. & Srivastava, M. Regulators of IAP function: coming to grips with the grim reaper. Curr. Opin. Cell Biol. 15, 717?724 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Fraser, A. G., James, C., Evan, G. I. & Hengartner, M. O. Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis. Curr. Biol. 9, 292?301 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Speliotes, E. K., Uren, A., Vaux, D. & Horvitz, H. R. The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol. Cell 6, 211?223 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Bloss, T. A., Witze, E. S. & Rothman, J. H. Suppression of CED-3-independent apoptosis by mitochondrial βNAC in Caenorhabditis elegans. Nature 424, 1066?1071 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Rospert, S., Dubaquie, Y. & Gautschi, M. Nascent-polypeptide-associated complex. Cell. Mol. Life Sci. 59, 1632?1639 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Takacs-Vellai, K. et al. Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans. Curr. Biol. 15, 1513?1517 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Yin, V. P. & Thummel, C. S. A balance between the diap1 death inhibitor and reaper and hid death inducers controls steroid-triggered cell death in Drosophila. Proc. Natl Acad. Sci. USA 101, 8022?8027 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ellis, R. E. & Horvitz, H. R. Two C. elegans genes control the programmed deaths of specific cells in the pharynx. Development 112, 591?603 (1991).

    CAS  PubMed  Google Scholar 

  74. Metzstein, M. M., Hengartner, M. O., Tsung, N., Ellis, R. E. & Horvitz, H. R. Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2. Nature 382, 545?547 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Metzstein, M. M. & Horvitz, H. R. The C. elegans cell death specification gene ces-1 encodes a snail family zinc finger protein. Mol. Cell 4, 309?319 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Nieto, M. A. The snail superfamily of zinc-finger transcription factors. Nature Rev. Mol. Cell Biol. 3, 155?166 (2002).

    Article  CAS  Google Scholar 

  77. Thellmann, M., Hatzold, J. & Conradt, B. The Snail-like CES-1 protein of C. elegans can block the expression of the BH3-only cell-death activator gene egl-1 by antagonizing the function of bHLH proteins. Development 130, 4057?4071 (2003). Convincing genetic and biochemical work that describes a transcriptional pathway that regulates apoptosis in the two sister cells of the NSM neurons in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  78. Seidel, M. G. & Look, A. T. E2A?HLF usurps control of evolutionarily conserved survival pathways. Oncogene 20, 5718?5725 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Wu, W. S. et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641?653 (2005). Recent publication that supports the idea that some of the pathways that regulate apoptosis are conserved from C. elegans to mammals.

    Article  CAS  PubMed  Google Scholar 

  80. Conradt, B. & Horvitz, H. R. The TRA-1A sex determination protein of C. elegans regulates sexually dimorphic cell deaths by repressing the egl-1 cell death activator gene. Cell 98, 317?327 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Hoeppner, D. J. et al. eor-1 and eor-2 are required for cell-specific apoptotic death in C. elegans. Dev. Biol. 274, 125?138 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Karashima, T., Sugimoto, A. & Yamamoto, M. Caenorhabditis elegans homologue of the human azoospermia factor DAZ is required for oogenesis but not for spermatogenesis. Development 127, 1069?1079 (2000).

    CAS  PubMed  Google Scholar 

  83. Navarro, R. E., Shim, E. Y., Kohara, Y., Singson, A. & Blackwell, T. K. cgh-1, a conserved predicted RNA helicase required for gametogenesis and protection from physiological germline apoptosis in C. elegans. Development 128, 3221?3232 (2001).

    CAS  PubMed  Google Scholar 

  84. Lettre, G. et al. Genome-wide RNAi identifies p53-dependent and -independent regulators of germ cell apoptosis in C. elegans. Cell Death Differ. 11, 1198?1203 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Boag, P. R., Nakamura, A. & Blackwell, T. K. A conserved RNA?protein complex component involved in physiological germline apoptosis regulation in C. elegans. Development 132, 4975?4986 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Gartner, A., Milstein, S., Ahmed, S., Hodgkin, J. & Hengartner, M. O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans. Mol. Cell 5, 435?443 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Ahmed, S. & Hodgkin, J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403, 159?164 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Ahmed, S., Alpi, A., Hengartner, M. O. & Gartner, A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein. Curr. Biol. 11, 1934?1944 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Derry, W. B., Putzke, A. P. & Rothman, J. H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294, 591?595 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Schumacher, B., Hofmann, K., Boulton, S. & Gartner, A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr. Biol. 11, 1722?1727 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Hofmann, E. R. et al. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Curr. Biol. 12, 1908?1918 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Bergamaschi, D. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genet. 33, 162?167 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Deng, X. et al. Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation. Nature Genet. 36, 906?912 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Boulton, S. J. et al. BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans. Curr. Biol. 14, 33?39 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Schumacher, B. et al. Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis. Cell 120, 357?368 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053?1058 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683?694 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Marin-Teva, J. L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535?547 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. White, K. et al. Genetic control of programmed cell death in Drosophila. Science 264, 677?683 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Lindsten, T. et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol. Cell 6, 1389?1399 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kurz, C. L. & Ewbank, J. J. Caenorhabditis elegans: an emerging genetic model for the study of innate immunity. Nature Rev. Genet. 4, 380?390 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Aballay, A. & Ausubel, F. M. Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis elegans from Salmonella typhimurium-mediated killing. Proc. Natl Acad. Sci. USA 98, 2735?2739 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kinchen, J. M. et al. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 434, 93?99 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Kinchen, J. M. & Hengartner, M. O. Tales of cannibalism, suicide, and murder: programmed cell death in C. elegans. Curr. Top. Dev. Biol. 65, 1?45 (2005).

    CAS  PubMed  Google Scholar 

  105. Hengartner, M. O. Apoptosis: corralling the corpses. Cell 104, 325?328 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Tilly, J. L. Commuting the death sentence: how oocytes strive to survive. Nature Rev. Mol. Cell Biol. 2, 838?848 (2001).

    Article  CAS  Google Scholar 

  107. Kim, M. R. & Tilly, J. L. Current concepts in Bcl-2 family member regulation of female germ cell development and survival. Biochim. Biophys. Acta 1644, 205?210 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Aballay, A., Drenkard, E., Hilbun, L. R. & Ausubel, F. M. Caenorhabditis elegans innate immune response triggered by Salmonella enterica requires intact LPS and is mediated by a MAPK signaling pathway. Curr. Biol. 13, 47?52 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Tenor, J. L., McCormick, B. A., Ausubel, F. M. & Aballay, A. Caenorhabditis elegans-based screen identifies Salmonella virulence factors required for conserved host?pathogen interactions. Curr. Biol. 14, 1018?1024 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank L. Neukomm for providing Fig. 1a, and K. Doukoumetzidis and N. C. Franc for help with Table 1. G.L. thanks the Fonds Québécois de la Recherche sur la Nature et les Technologies for financial support.

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Glossary

Autophagy

A pathway for the recycling of cellular contents, in which materials inside the cell are packaged into vesicles and are then targeted to the vacuole or lysosome for bulk turnover.

Phagolysosome

A cellular body that is formed by the union of a phagosome or ingested particle with a lysosome that contains hydrolytic enzymes.

1.5-fold stage

A C. elegans developmental stage that occurs 420?460 minutes after the first cleavage at 20 °C. The cell number remains at 560 cells, with some new cells generated and some cells going through programmed cell death. The shape of the embryo is elongated and folds back on itself by 50%.

Caspase family

A family of Cys proteases that cleave after Asp residues. Initiator caspases are typically activated in response to particular stimuli, whereas effector caspases are particularly important for the ordered dismantling of vital cellular structures.

Apoptosome

In mammalian cells, the apoptosome is a complex that forms when cytochrome c is released from mitochondria and interacts with the cytosolic protein APAF1, which, in turn, recruits pro-caspase-9. In the presence of ATP, this interaction results in the allosteric activation of caspase-9 and in the formation of a caspase-3-activation complex.

Bcl-2 family

Anti- and pro-apoptotic proteins that, in mammals, control mitochondrial-membrane permeabilization, a key event in apoptosis. The members of this family share characteristic domains of homology known as Bcl-2 homology (BH) domains.

Bcl-2 homology (BH) domains

Sequence analysis of the proteins in the Bcl-2 family has identified four BH domains (BH1?BH4). These domains contribute at several levels to the function of the members of the Bcl-2 family in cell death and survival.

BH3-only-domain protein

Sequence alignment among the Bcl-2-family proteins has identified four Bcl-2 homology (BH) domains, BH1?BH4. The BH3-only members contain a single BH3 domain and are pro-apoptotic.

WD40 domain

A 40-amino-acid-long protein motif that contains a WD dipeptide at its carboxyl terminus. This domain is found in many functionally diverse proteins and mediates protein?protein interactions.

Mitochondrial fission

Mitochondrial division is a protein-driven process that regulates, with mitochondrial fusion, the dynamics of the mitochondrial network in mammalian cells. Recent evidence suggests that mitochondrial fragmentation might also have an active role in apoptosis.

Baculovirus IAP repeat (BIR) domain

Cysteine-based motif of 65 amino acids. Inhibitors of apoptosis (IAPs) contain several BIR domains.

RING-finger domain

A protein domain that consists of two loops that are held together at their base by Cys and His residues, which form a complex with two zinc ions. Many RING fingers function in protein degradation by facilitating protein ubiquitylation.

Epistasis analysis

Epistasis is the masking of a phenotype that is caused by a mutation in one gene by a mutation in another gene. Epistasis analysis can therefore be used to dissect the order in which the genes in a genetic pathway act.

Caspase-recruitment domain

(CARD). A conserved domain that is found in c-IAP1 and c-IAP2. The function of the domain in these molecules is unknown at present.

Serotonergic

Describes a nerve that functions by the release of serotonin from the nerve endings.

Zinc-finger transcription factors

Zinc-finger domains are found in numerous nucleic-acid-binding proteins. The zinc-finger motif is an unusually small, self-folding domain in which zinc is a crucial component of its tertiary structure.

Basic-region leucine zipper

(bZIP). A basic leucine-zipper motif that is often associated with transcription factors. Dimerization through the leucine zipper is required for DNA binding. Hetero- or homodimers lend further complexity to the regulation of transcription by members of this family, which include Fos, Jun and the cAMP-responsive-element-binding protein/activating transcription factor (CREB/ATF) family members.

Basic helix?loop?helix (bHLH) transcription factor

A protein that contains two α-helices separated by a loop (the HLH domain), which binds DNA in a sequence-specific manner.

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Lettre, G., Hengartner, M. Developmental apoptosis in C. elegans: a complex CEDnario. Nat Rev Mol Cell Biol 7, 97–108 (2006). https://doi.org/10.1038/nrm1836

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