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Phagocytosis promotes programmed cell death in C. elegans

Nature volume 412, pages 198–202 (2001)Cite this article

Abstract

In the nematode Caenorhabditis elegans programmed cell death requires the killer genes egl-1, ced-4 and ced-3 (refs 1 and 2), and the engulfment of dying cells requires the genes ced-1, ced-2, ced-5, ced-6, ced-7, ced-10 and ced-12 (refs 3,4,5). Here we show that engulfment promotes programmed cell death. Mutations that cause partial loss of function of killer genes allow the survival of some cells that are programmed to die, and mutations in engulfment genes enhance the frequency of this cell survival. Furthermore, mutations in engulfment genes alone allow the survival and differentiation of some cells that would normally die. Engulfment genes probably act in engulfing cells to promote death, as the expression in engulfing cells of ced-1, which encodes a receptor that recognizes cell corpses6, rescues the cell-killing defects of ced-1 mutants. We propose that engulfing cells act to ensure that cells triggered to undergo programmed cell death by the CED-3 caspase7 die rather than recover after the initial stages of death.

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Figure 1: Engulfment mutations lead to the survival of cells programmed to die in the ventral cord.
Figure 2: ced-1 acts in engulfing cells to control cell killing.

References

  1. Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986).

    Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. 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  ADS  CAS  Google Scholar 

  4. 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 

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

    Article  CAS  Google Scholar 

  6. Zhou, Z., Hartwieg, E. & Horvitz, H. R. CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104, 43–56 (2001).

    Article  CAS  Google Scholar 

  7. 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-1 beta-converting enzyme. Cell 75, 641–652 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. 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 

  10. Robertson, A. M. G. & Thomson, J. N. Morphology of programmed cell death in the ventral nerve cord of C. elegans larvae. J. Embryol. Exp. Morphol. 67, 89–100 (1982).

    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  Google Scholar 

  12. Albert, M. L., Kim, J. I. & Birge, R. B. alpha Vβ5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nature Cell Biol. 2, 899–905 (2000).

    Article  CAS  Google Scholar 

  13. 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 

  14. 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 

  15. Wu, Y. C. & Horvitz, H. R. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392, 501–504 (1998).

    Article  ADS  CAS  Google Scholar 

  16. Reddien, P. W. & Horvitz, H. R. CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nature Cell Biol. 2, 131–136 (2000).

    Article  CAS  Google Scholar 

  17. 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 

  18. Freyd, G., Kim, S. K. & Horvitz, H. R. Novel cysteine-rich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11. Nature 344, 876–879 (1990).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. 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  Google Scholar 

  21. 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 

  22. 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 

  23. Sulston, J. E., Albertson, D. G. & Thomson, J. N. The Caenorhabditis elegans male: postembryonic development of nongonadal structures. Dev. Biol. 78, 542–576 (1980).

    Article  CAS  Google Scholar 

  24. Wu, Y. C., Stanfield, G. M. & Horvitz, H. R. NUC-1, a Caenorhabditis elegans DNase II homolog, functions in an intermediate step of DNA degradation during apoptosis. Genes Dev. 14, 536–548 (2000).

    CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  26. Lang, R. A. & Bishop, J. M. Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 74, 453–462 (1993).

    Article  CAS  Google Scholar 

  27. Little, G. H. & Flores, A. Inhibition of programmed cell death by catalase and phenylalanine methyl ester. Comp. Biochem. Physiol. Physiol. 105, 79–83 (1993).

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  29. Clark, S. G., Lu, X. & Horvitz, H. R. The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins. Genetics 137, 987–997 (1994).

    CAS  Google Scholar 

  30. Hobert, O. et al. Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron 19, 345–357 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. Galvin, B. Hersh and Z. Zhou for comments. P.W.R. was supported by a National Science Foundation Fellowship. S.C. was supported by a Howard Hughes Medical Institute (HHMI) postdoctoral fellowship, a Merck/MIT collaborative fellowship, and an NIH training grant. H.R.H. is an Investigator of the HHMI.

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Authors and Affiliations

  1. Department of Biology, Howard Hughes Medical Institute, 68-425, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Peter W. Reddien, Scott Cameron & H. Robert Horvitz

  2. Division of Pediatric Hematology Oncology, Children's Hospital/Dana Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Scott Cameron

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  1. Peter W. Reddien
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  3. H. Robert Horvitz
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Correspondence to H. Robert Horvitz.

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Reddien, P., Cameron, S. & Horvitz, H. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001). https://doi.org/10.1038/35084096

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