Cell Death in C. elegans


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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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]