Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans

Nature volume 412, pages 202–206 (2001)Cite this article

Abstract

Genetic studies have identified over a dozen genes that function in programmed cell death (apoptosis) in the nematode Caenorhabditis elegans1,2,3. Although the ultimate effects on cell survival or engulfment of mutations in each cell death gene have been extensively described, much less is known about how these mutations affect the kinetics of death and engulfment, or the interactions between these two processes. We have used four-dimensional-Nomarski time-lapse video microscopy to follow in detail how cell death genes regulate the extent and kinetics of apoptotic cell death and removal in the early C. elegans embryo. Here we show that blocking engulfment enhances cell survival when cells are subjected to weak pro-apoptotic signals. Thus, genes that mediate corpse removal can also function to actively kill cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Fate distribution of early AB lineage deaths in wild-type and mutant backgrounds.
Figure 2: Mutations in ced genes affect the kinetics of killing and engulfment.
Figure 3: Engulfment promotes cell death in weak ced-3 mutant backgrounds.
Figure 4: Possible modes of interaction between killing and engulfment.

Similar content being viewed by others

References

  1. 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  Google Scholar 

  2. Hengartner, M. O. in C. elegans II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 383–415 (Cold Spring Harbor Laboratory, Cold Spring Harbor, 1997).

    Google Scholar 

  3. Gumienny, T. L. & Hengartner, M. How the worm removes corpses: the nematode C. elegans as a model system to study engulfment. Cell Death Diff. (in the press).

  4. Schnabel, R., Hutter, H., Moerman, D. & Schnabel, H. Assessing normal embryogenesis in Caenorhabditis elegans using a 4D microscope: variability of development and regional specification. Dev. Biol. 184, 234–265 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Robertson, A. & Thomson, N. Morphology of programmed cell death in the ventral nerve cord of Caenorhabditis elegans larvae. J. Embryol. Exp. Morph. 67, 89–100 (1982).

    Google Scholar 

  7. 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  Google Scholar 

  8. 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  Google Scholar 

  9. Liu, Q. A. & Hengartner, M. O. Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans. Cell 93, 961–972 (1998).

    Article  CAS  Google Scholar 

  10. Wu, Y.-C. & Horvitz, H. R. The C. elegans cell-corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93, 951–960 (1998).

    Article  CAS  Google Scholar 

  11. Stanfield, G. M. & Horvitz, H. R. The ced-8 gene controls the timing of programmed cell deaths in C. elegans. Mol. Cell 5, 423–433 (2000).

    Article  CAS  Google Scholar 

  12. Miller, L. K. An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol. 9, 323–328 (1999).

    Article  CAS  Google Scholar 

  13. 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  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  15. Shaham, S., Reddien, P. W., Davies, B. & Horvitz, H. R. Mutational analysis of the Caenorhabditis elegans cell-death gene ced-3. Genetics 153, 1655–1671 (1999).

    CAS  Google Scholar 

  16. Knepper-Nicolai, B., Savill, J. & Brown, S. B. Constitutive apoptosis in human neutrophils requires synergy between calpains and the proteasome downstream of caspases. J. Biol. Chem. 273, 30530–30536 (1998).

    Article  CAS  Google Scholar 

  17. Lang, R., Lustig, M., Francois, F., Sellinger, M. & Plesken, H. Apoptosis during macrophage-dependent ocular tissue remodelling. Development 120, 3395–3403 (1994).

    CAS  Google Scholar 

  18. Diez-Roux, G. & Lang, R. A. Macrophages induce apoptosis in normal cells in vivo. Development 124, 3633–3638 (1997).

    CAS  Google Scholar 

  19. Duffield, J. S. et al. Activated macrophages direct apoptosis and suppress mitosis of mesangial cells. J. Immunol. 164, 2110–2119 (2000).

    Article  CAS  Google Scholar 

  20. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  Google Scholar 

  21. Chung, S., Gumienny, T. L., Hengartner, M. O. & Driscoll, M. A common set of genes mediate removal of both apoptotic and necrotic cell corpses in C. elegans. Nature Cell Biol. 2, 931–937 (2000).

    Article  CAS  Google Scholar 

  22. 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  ADS  CAS  Google Scholar 

  23. Hodgkin, J. in C. elegans II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 881–1047 (Cold Spring Harbor Laboratory, Plainview, 1997).

    Google Scholar 

Download references

Acknowledgements

We thank P. Reddien and R. Horvitz for sharing results before publication, and G. Chimini, V. Fadok, N. Franc, R. Lang, J. Savill, P. Williamson, and members of the Hengartner laboratory for useful comments. This work was supported by an NIH grant and a research grant from Devgen NV to M.O.H.

Author information

Author notes

  1. Ralf Schnabel

    Present address: Institut fuer Genetik, TU Braunschweig, Spielmannstrasse 7, Braunschweig, D-38106, Germany

  2. Daniel J. Hoeppner

    Present address: NINDS-LMB, Building 36, National Institutes of Health, Bethesda, Maryland, 20892-4092, USA

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, 11724, New York, USA

    Daniel J. Hoeppner & Michael O. Hengartner

  2. Department of Molecular Genetics and Microbiology, Graduate Program in Genetics, SUNY at Stony Brook, Stony Brook, 11794, New York, USA

    Daniel J. Hoeppner

Authors
  1. Daniel J. Hoeppner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael O. Hengartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ralf Schnabel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael O. Hengartner.

Supplementary information

Table 1 and 2 figures, all with legends.

Movie 1. Wild type Grandmother (ABalppaa)

Unlike mitoses leading immediately to a dying cell, most mitoses produce two daughters of approximately equivalent size, as shown here.

Movie 2. Wild type (ABalppaap)

Demonstrates normal birth, onset, death and engulfment

Movie 3. ced-7(n1892) (ABprpppapp)

Demonstrates birth, onset, death and delayed engulfment

Movie 4. ced-3(op149) (ABplpppapp)

Demonstrates birth, onset, reversion, no death, no engulfment, ectopic mitosis

Movie 5. ced-7(n1892); ced-3(op149) (ABplpappap)

Demonstrates birth, no death, no engulfment

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoeppner, D., Hengartner, M. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 (2001). https://doi.org/10.1038/35084103

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35084103

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing