Cell Death in C. elegans

Abstract

Programmed cell death plays a central role in the development of most multicellular animals. During the development of Caenorhabditis elegans, a total of 1090 cells are generated, 131 of which are destined to die. Genetic studies focusing on the control of the fate of these 131 cells revealed an evolutionary conserved set of genes essential for all programmed cell deaths in C. elegans. In a cell undergoing apoptosis, the BH3‐only domain protein EGL‐1 binds to the CED‐9–CED‐4 complex on the outer mitochondrial membrane resulting in the release of CED‐4, which in turn activates the effector caspase CED‐3. These at the time pioneering findings established C. elegans as a prime model system to study apoptosis, a system that still today provides a stage for new inspiring science, such as studies on C. elegans apoptotic cell clearance and on deoxyribonucleic acid (DNA) damage‐induced apoptosis.

Key concepts:

  • Caenorhabditis elegans as a model organism has been introduced by Sidney Brenner in the 1960s.

  • The complete C. elegans cell lineage was described in 1983 by John Sulston.

  • The cell lineage in C. elegans is invariant: during the development of an animal, a total of 1090 cells are generated, 131 of which are destined to die.

  • The basis for analysing programmed cell death in C. elegans was delineation of the complete cell lineage.

  • There are three waves of programmed cell death in C. elegans: a first wave can be observed in embryos, the second smaller wave during the second larval stage, whereas the third wave occurs in the adult germline.

  • Germline apoptosis is a stochastic process in which half of the germ cells undergo apoptotic cell death.

  • CED‐4 and CED‐3 are killer proteins essential for all programmed cell deaths in C. elegans.

  • CED‐9 is homologous to Bcl‐2 and protects from cell death.

  • In a cell undergoing apoptosis, the BH3‐only domain protein EGL‐1 inhibits CED‐9 from inhibiting CED‐4.

  • The central cell death pathway is conserved through evolution; homologues of EGL‐1, CED‐9, CED‐4 and CED‐3 are present in mammals, where they control the mitochondrial pathway for apoptosis.

  • Apoptotic cell clearance is controlled via two partially redundant intracellular signalling cascades that converge at the Rac1 homologue CED‐10.

  • DNA damage‐induced germline apoptosis is triggered by a genomic integrity checkpoint and activates a pathway including the p53 homologue CEP‐1.

Keywords: C. elegans; cell lineage; developmental apoptosis; engulfment; germline apoptosis; DNA damage‐induced apoptosis

Figure 1.

The cell lineage of C. elegans. The complete C. elegans cell lineage (pattern of cell divisions from the zygote to the adult hermaphrodite). In the magnified panel, cells that are doomed to die are highlighted with a red circle. Adapted from Sulston et al..

Figure 2.

Developmental and germline apoptosis in C. elegans. Developmental and germline apoptosis in C. elegans, as visualized by Nomarski (DIC) optics. A first major wave of developmental cell death is observed in embryos 250–450 min after fertilization where 113 cells die (right side). At the second larval stage, another 18 somatic cells undergo programmed cell death. The third wave of apoptosis occurs in the pachytene region of the adult gonad (left side), where approximately half of the germ cells die by apoptosis. Arrows indicate apoptotic cell corpses.

Figure 3.

A conserved genetic pathway for developmental programmed cell death in C. elegans. Programmed cell death includes three distinct steps: the decision to die, engulfment of the apoptotic cell and degradation of the engulfed cell. The core apoptotic machinery consists of egl‐1, ced‐9, ced‐4 and ced‐3 and is activated by tissue‐specific developmental cues. Apoptotic cells are then engulfed by neighbouring cells due to activation of two partially redundant pathways – ced‐1, ced‐6, ced‐7 and ced‐2, ced‐5, ced‐12, which converge at the Rac1 homologue ced‐10. Degradation of engulfed cells depend on different genes such as nuc‐1, an endonuclease that was the first identified cell death mutant in C. elegans (Ellis et al., ).

Figure 4.

Molecular model of apoptosis induction and cell corpse removal in C. elegans. Apoptosis is initiated by the BH3‐only domain protein EGL‐1, which binds to the CED‐9–CED‐4 complex on the outer mitochondrial membrane (1). Upon EGL‐1 binding, CED‐4 dimer is released from CED‐9 and recruits proCED‐3 molecules to build the so‐called apoptosome (2). CED‐3 activation (4) occurs by proteolytic cleavage (3). Removal of the apoptotic cell is triggered by receptor‐mediated recognition of ‘eat‐me’ signals such as phosphatidylserine (5). Intracellular signalling that drives engulfment of the dying cell involves two partially redundant pathways consisting of unc‐73, mig‐2, ced2, ced‐5, ced‐12 (6) and ced‐1, ced‐6, ced‐7 (7). These two signalling pathways may converge at the Rac1 homologue CED‐10 to regulate actin reorganization (8).

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References

Ahmed S, Alpi A, Hengartner MO and Gartner A (2001) C. elegans RAD‐5/CLK‐2 defines a new DNA damage checkpoint protein. Current Biology 11(24): 1934–1944.

Ahmed S and Hodgkin J (2000) MRT‐2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403(6766): 159–164. doi:10.1038/35003120.

Avery L and Horvitz HR (1987) A cell that dies during wild‐type C. elegans development can function as a neuron in a ced‐3 mutant. Cell 51(6): 1071–1078.

Bergamaschi D, Samuels Y, O'Neil NJ et al. (2003) iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genetics 33(2): 162–167. doi:10.1038/ng1070.

Chan SL, Yee KS, Tan KM and Yu VC (2000) The Caenorhabditis elegans sex determination protein FEM‐1 is a CED‐3 substrate that associates with CED‐4 and mediates apoptosis in mammalian cells. Journal of Biological Chemistry 275(24): 17925–17928. doi:10.1074/jbc.C000146200.

Chen F, Hersh BM, Conradt B et al. (2000) Translocation of C. elegans CED‐4 to nuclear membranes during programmed cell death. Science 287(5457): 1485–1489.

Chung S, Gumienny TL, Hengartner MO and Driscoll M (2000) A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans. Nature Cell Biology 2(12): 931–937. doi:10.1038/35046585.

Conradt B and Horvitz HR (1998) The C. elegans protein EGL‐1 is required for programmed cell death and interacts with the Bcl‐2‐like protein CED‐9. Cell 93(4): 519–529.

Conradt B and Xue D (2005) Programmed cell death. WormBook: The Online Review of C. elegans Biology   1–13. doi:10.1895/wormbook.1.32.1.

del Peso L, Gonzalez VM, Inohara N, Ellis RE and Núñez G (2000) Disruption of the CED‐9‐CED‐4 complex by EGL‐1 is a critical step for programmed cell death in Caenorhabditis elegans. Journal of Biological Chemistry 275(35): 27205–27211. doi:10.1074/jbc.M000858200.

Derry WB, Putzke AP and Rothman JH (2001) Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294(5542): 591–595. doi:10.1126/science.1065486.

Ellis HM and Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6): 817–829.

Ellis RE, Jacobson DM and Horvitz HR (1991) Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129(1): 79–94.

Fadok VA, de Cathelineau A, Daleke DL, Henson PM and Bratton DL (2001) Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. Journal of Biological Chemistry 276(2): 1071–1077. doi:10.1074/jbc.M003649200.

Gartner A, Milstein S, Ahmed S, Hodgkin J and Hengartner MO (2000) A conserved checkpoint pathway mediates DNA damage – induced apoptosis and cell cycle arrest in C. elegans. Molecular Cell 5(3): 435–443.

Gartner A, Boag PR and Blackwell TK (2008) Germline survival and apoptosis. WormBook: The Online Review of C. elegans Biology   1–20. doi:10.1895/wormbook.1.145.1.

Green Z, Reed JC and Douglas R (1998) Mitochondria and apoptosis. Science 281(5381): 1309–1312. doi:10.1126/science.281.5381.1309.

Gumienny TL, Lambie E, Hartwieg E, Horvitz HR and Hengartner MO (1999) Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126(5): 1011–1022.

Hengartner MO, Ellis RE and Horvitz HR (1992) Caenorhabditis elegans gene ced‐9 protects cells from programmed cell death. Nature 356(6369): 494–499. doi:10.1038/356494a0.

Hofmann ER, Milstein S, Boulton SJ et al. (2002) Caenorhabditis elegans HUS‐1 is a DNA damage checkpoint protein required for genome stability and EGL‐1‐mediated apoptosis. Current Biology 12(22): 1908–1918.

Hu Y, Ding L, Spencer DM and Núñez G (1998) WD‐40 repeat region regulates Apaf‐1 self‐association and procaspase‐9 activation. Journal of Biological Chemistry 273(50): 33489–33494.

Kerr JF, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide‐ranging implications in tissue kinetics. British Journal of Cancer 26(4): 239–257.

Kinchen JM and Ravichandran KS (2007) Journey to the grave: signaling events regulating removal of apoptotic cells. Journal of Cell Science 120(13): 2143–2149. doi:10.1242/jcs.03463.

Lettre G and Hengartner MO (2006) Developmental apoptosis in C. elegans: a complex CEDnario. Nature Reviews. Molecular Cell Biology 7(2): 97–108. doi:10.1038/nrm1836.

Li P, Nijhawan D, Budihardjo I et al. (1997) Cytochrome c and dATP‐dependent formation of Apaf‐1/caspase‐9 complex initiates an apoptotic protease cascade. Cell 91(4): 479–489.

Nietzsche F (1892) Die fröhliche Wissenschaft “la gaya scienza”. Ernst Schmeitzner Verlag.

Oda E, Ohki R, Murasawa H et al. (2000) Noxa, a BH3‐only member of the Bcl‐2 family and candidate mediator of p53‐induced apoptosis. Science 288(5468): 1053–1058.

Quevedo C, Kaplan DR and Brent Derry W (2007) AKT‐1 regulates DNA‐damage‐induced germline apoptosis in C. elegans. Current Biology 17(3): 286–292. doi:10.1016/j.cub.2006.12.038.

Schlegel RA, Callahan M, Krahling S, Pradhan D and Williamson P (1996) Mechanisms for recognition and phagocytosis of apoptotic lymphocytes by macrophages. Advances in Experimental Medicine and Biology 406: 21–28.

Schumacher B, Schertel C, Wittenburg N et al. (2005a) C. elegans ced‐13 can promote apoptosis and is induced in response to DNA damage. Cell Death and Differentiation 12(2): 153–161. doi:10.1038/sj.cdd.4401539.

Schumacher B, Hanazawa M, Lee M‐H et al. (2005b) Translational repression of C. elegans p53 by GLD‐1 regulates DNA damage‐induced apoptosis. Cell 120(3): 357–368. doi:10.1016/j.cell.2004.12.009.

Shaham S and Horvitz HR (1996) An alternatively spliced C. elegans ced‐4 RNA encodes a novel cell death inhibitor. Cell 86(2): 201–208.

Spector MS, Desnoyers S, Hoeppner DJ and Hengartner MO (1997) Interaction between the C. elegans cell‐death regulators CED‐9 and CED‐4. Nature 385(6617): 653–656. doi:10.1038/385653a0.

Stergiou L and Hengartner MO (2004) Death and more: DNA damage response pathways in the nematode C. elegans. Cell Death and Differentiation 11(1): 21–28. doi:10.1038/sj.cdd.4401340.

Suh E‐K, Yang A, Kettenbach A et al. (2006) p63 protects the female germ line during meiotic arrest. Nature 444(7119): 624–628. doi:10.1038/nature05337.

Sulston JE and Horvitz HR (1977) Post‐embryonic cell lineages of the nematode, Caenorhabditis elegans. Developmental Biology 56(1): 110–156.

Sulston JE and Horvitz HR (1981) Abnormal cell lineages in mutants of the nematode Caenorhabditis elegans. Developmental Biology 82(1): 41–55.

Sulston JE, Schierenberg E, White JG and Thomson JN (1983a) The embryonic cell lineage of the nematode Caenorhabditis elegans. Developmental Biology 100(1): 64–119.

Sulston JE, Schierenberg E, White JG and Thomson JN (1983b) The embryonic cell lineage of the nematode Caenorhabditis elegans. Developmental Biology 100(1): 64–119.

Taylor RC, Brumatti G, Ito S et al. (2007) Establishing a blueprint for CED‐3‐dependent killing through identification of multiple substrates for this protease. Journal of Biological Chemistry 282(20): 15011–15021. doi:10.1074/jbc.M611051200.

Wu D, Wallen HD and Nuñez G (1997a) Interaction and regulation of subcellular localization of CED‐4 by CED‐9. Science 275(5303): 1126–1129.

Wu D, Wallen HD, Inohara N and Nuñez G (1997b) Interaction and regulation of the Caenorhabditis elegans death protease CED‐3 by CED‐4 and CED‐9. Journal of Biological Chemistry 272(34): 21449–21454.

Xue D and Horvitz HR (1997) Caenorhabditis elegans CED‐9 protein is a bifunctional cell‐death inhibitor. Nature 390(6657): 305–308. doi:10.1038/36889.

Yan N, Chai J, Lee ES et al. (2005) Structure of the CED‐4‐CED‐9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 437(7060): 831–837. doi:10.1038/nature04002.

Yang X, Chang HY and Baltimore D (1998) Essential role of CED‐4 oligomerization in CED‐3 activation and apoptosis. Science 281(5381): 1355–1357.

Yuan JY and Horvitz HR (1990) The Caenorhabditis elegans genes ced‐3 and ced‐4 act cell autonomously to cause programmed cell death. Developmental Biology 138(1): 33–41.

Yuan J and Horvitz HR (1992) 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(2): 309–320.

Zhang Y and Xiong Y (2001) Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth & Differentiation: The Molecular Biology Journal of the American Association for Cancer Research 12(4): 175–186.

Züllig S, Neukomm LJ, Jovanovic M et al. (2007) Aminophospholipid translocase TAT‐1 promotes phosphatidylserine exposure during C. elegans apoptosis. Current Biology 17(11): 994–999. doi:10.1016/j.cub.2007.05.024.

Further Reading

Mangahas PM and Zhou Z (2005) Clearance of apoptotic cells in Caenorhabditis elegans. Seminars in Cell & Developmental Biology 16(2): 295–306. doi:10.1016/j.semcdb.2004.12.005.

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Sendoel, Ataman, and Hengartner, Michael O(Dec 2009) Cell Death in C. elegans. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021563]