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.

Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans

Nature volume 434, pages 93–99 (2005)Cite this article

Abstract

The removal of apoptotic cells is essential for the physiological well being of the organism1,2,3. In Caenorhabditis elegans, two conserved, partially redundant genetic pathways regulate this process4,5,6. In the first pathway, the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1)7,8. In the second group, the candidate receptor CED-1 (CD91/LRP/SREC) probably recognizes an unknown ligand on the apoptotic cell9 and signals via its cytoplasmic tail to the adaptor protein CED-6 (hCED-6/GULP)10,11, whereas CED-7 (ABCA1) is thought to play a role in membrane dynamics12. Molecular understanding of how the second pathway promotes engulfment of the apoptotic cell is lacking. Here, we show that CED-1, CED-6 and CED-7 are required for actin reorganization around the apoptotic cell corpse, and that CED-1 and CED-6 colocalize with each other and with actin around the dead cell. Furthermore, we find that the CED-10(Rac) GTPase acts genetically downstream of these proteins to mediate corpse removal, functionally linking the two engulfment pathways and identifying the CED-1, -6 and -7 signalling module as upstream regulators of Rac activation.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Recruitment of actin halos around apoptotic cells in the hermaphrodite germ line requires CED-1 and CED-7.
Figure 2: CED-1 recruits CED-6 and actin around the apoptotic cell.

References

  1. Savill, J. & Fadok, V. Corpse clearance defines the meaning of cell death. Nature 407, 784–788 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Scott, R. S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. Gumienny, T. L. et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107, 27–41 (2001)

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Conradt, B. Cell engulfment, no sooner ced than done. Dev. Cell 1, 445–447 (2001)

    Article  CAS  PubMed  Google Scholar 

  8. Brugnera, E. et al. Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nature Cell Biol. 4, 574–582 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. Su, H. P. et al. Interaction of CED-6/GULP, an adapter protein involved in engulfment of apoptotic cells with CED-1 and CD91/low density lipoprotein receptor-related protein (LRP). J. Biol. Chem. 277, 11772–11779 (2002)

    Article  CAS  PubMed  Google Scholar 

  12. Hamon, Y., Chambenoit, O. & Chimini, G. ABCA1 and the engulfment of apoptotic cells. Biochim. Biophys. Acta 1585, 64–71 (2002)

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Stergiou, L. & Hengartner, M. O. Death and more: DNA damage response pathways in the nematode C. elegans. Cell Death Differ. 11, 21–28 (2004)

    Article  CAS  PubMed  Google Scholar 

  15. 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  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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 

  17. 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  ADS  CAS  PubMed  Google Scholar 

  18. 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  PubMed  PubMed Central  Google Scholar 

  19. Lundquist, E. A., Reddien, P. W., Hartwieg, E., Horvitz, H. R. & Bargmann, C. I. Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis. Development 128, 4475–4488 (2001)

    CAS  PubMed  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Liu, Q. A. & Hengartner, M. O. Human CED-6 encodes a functional homologue of the Caenorhabditis elegans engulfment protein CED-6. Curr. Biol. 9, 1347–1350 (1999)

    Article  CAS  PubMed  Google Scholar 

  22. Wu, Y. C., Tsai, M. C., Cheng, L. C., Chou, C. J. & Weng, N. Y. C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pathway to control cell migration and cell corpse engulfment. Dev. Cell 1, 491–502 (2001)

    Article  CAS  PubMed  Google Scholar 

  23. Soto, M. C. et al. The GEX-2 and GEX-3 proteins are required for tissue morphogenesis and cell migrations in C. elegans. Genes Dev. 16, 620–632 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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  PubMed  Google Scholar 

  25. Herz, J. & Strickland, D. K. LRP: a multifunctional scavenger and signaling receptor. J. Clin. Invest. 108, 779–784 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Harris, T. W. et al. WormBase: a cross-species database for comparative genomics. Nucleic Acids Res. 31, 133–137 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Praitis, V., Casey, E., Collar, D. & Austin, J. Creation of low-copy integrated transgenic lines in Caenorhabditis elegans. Genetics 157, 1217–1226 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mello, C. C., Kramer, J. M., Stinchcomb, D. T. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Strome, S. Fluorescence visualization of the distribution of microfilaments in gonads and early embryos of the nematode Caenorhabditis elegans. J. Cell Biol. 103, 2241–2252 (1986)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank K. S. Ravichandran, M. Spector, T. Gumienny and L. Stergiou for comments on this manuscript, S. Milstein for the use of the gla-1(op234) allele, O. Hobert for the gift of the Plim-7 plasmid, J. Austin for pDPMM0016 (unc-119(+ )), and P. Gisler for worm freezing. Some strains were supplied by the Caenorhabditis Genetic Center (CGC), which is supported by the National Institute of Health National Center for Research Resources. This work was supported by grants from the Swiss National Science Foundation, The Ernst Hadorn Foundation and the European Union (FP5 project APOCLEAR) to M.O.H., and by the Max Planck Society and an EU TMR Research Network grant to R.S.

Author information

Author notes

  1. Jason M. Kinchen

    Present address: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, 22908, USA

  2. Richard Feichtinger

    Present address: Xybermind GmbH, Lorettoplatz 26, D - 72072, Tübingen, Germany

  3. Heinke Schnabel

    Present address: Max Planck Institut für Neurobiologie, Am Klopferspitz 18A, D - 82152, Martinsried, Germany

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, New York, 11743, USA

    Jason M. Kinchen

  2. Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH - 8057, Zurich, Switzerland

    Jason M. Kinchen, Doris Klingele, Kelvin Wong & Michael O. Hengartner

  3. Institut für Genetik, TU Braunschweig, Spielmannstrasse 7, D - 38106, Braunschweig, Germany

    Juan Cabello & Ralf Schnabel

Authors
  1. Jason M. Kinchen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan Cabello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Doris Klingele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kelvin Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard Feichtinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heinke Schnabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ralf Schnabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael O. Hengartner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael O. Hengartner.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods

Additional description of methods used in paper. (DOC 23 kb)

Supplementary References

List of publications referenced in supplementary methods. (DOC 21 kb)

Supplementary Table 1

SYTO12 and SYTO41 specifically stain apoptotic cells in the hermaphrodite gonad. (DOC 23 kb)

Supplementary Table 2

CED-1 and CED-6 fusion proteins are functional. This table shows the ability of various transgenics to rescue the engulfment defects associated with various mutations to show functionality of FP-fusion proteins. (DOC 25 kb)

Supplementary Table 3

Overexpression of CED-10 cannot induce the formation of exogenous actin haloes. (DOC 25 kb)

Supplementary Table 4

Locations of lesions in genes used in Table 2 for double mutant analysis. (DOC 41 kb)

Supplementary Table 5

Corpses are still removed in a ced-10(t1875) mutant background. 4-D microscopy during embryogenesis in wild-type versuss ced-10(t1875) mutant worms suggests that although CED-10 is required for both engulfment pathway function, it is not required for engulfment per se, and a third salvage pathway may exist for the removal of apoptotic cell corpses. (DOC 52 kb)

Supplementary Table 6

Primers used for this study. (DOC 23 kb)

Supplementary Figure 1

YFP::Actin forms fibrous structures in the hermaphrodite somatic gonad. (DOC 354 kb)

Supplementary Figure 2

SYTO12 and SYTO41 specifically stain apoptotic cell corpses. (DOC 179 kb)

Supplementary Figure 3

CED-1 does not co-localize with actin fibers in the hermaphrodite somatic gonad. (DOC 75 kb)

Supplementary Figure 4

ced-10(t1875) has a mutated start codon. Diagram of lesions in the ced-10 locus used in this study, both at the DNA and at the protein level. (DOC 118 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kinchen, J., Cabello, J., Klingele, D. et al. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 434, 93–99 (2005). https://doi.org/10.1038/nature03263

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03263

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