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.

  • Progress
  • Published:

Mouse models of cell death

Nature Genetics volume 28, pages 113–118 (2001)Cite this article

Abstract

Cell death is critical for the development and orderly maintenance of cellular homeostasis in metazoans. Developmental genetics in model systems, including Caenorhabditis elegans and Drosophila melanogaster, have helped to identify and order the components of cell-death pathways. An even more complex network of apoptotic pathways has evolved in higher organisms that possess homologs within each set of cell-death regulators. Whereas biochemical studies provide details of molecular mechanisms, genetic models reveal the essential physiologic roles. Transgenic and gene-ablated mice have helped to elucidate mammalian apoptotic pathways and identify the principal effect of each cell death regulator. Here, we review the details of the apoptotic machinery as revealed by mice deficient in critical components of cell-death pathways; we concentrate on cell-death regulators classified as members of the caspase and Bcl2 families or, broadly, as adaptors and mitochondrial released factors.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Summary of anti- and pro-apoptotic Bcl2 family proteins.
Figure 2: Mammalian cell-death pathways; genes for which knockout mouse models reveal their physiological roles.

Similar content being viewed by others

References

  1. Kerr, J.F., Wyllie, A.H. & Currie, A.R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Pellegrini, M. & Strasser, A. A portrait of the Bcl-2 protein family: life, death, and the whole picture. J. Clin. Immunol. 19, 365–377 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Ellis, R.E., Yuan, J.Y. & Horvitz, H.R. Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Abrams, J.M. An emerging blueprint for apoptosis in Drosophila. Trends Cell Biol. 9, 435–440 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Martin, D.A., Siegel, R.M., Zheng, L. & Lenardo, M.J. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal. J. Biol. Chem. 273, 4345–4349 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Muzio, M., Stockwell, B.R., Stennicke, H.R., Salvesen, G.S. & Dixit, V.M. An induced proximity model for caspase-8 activation. J. Biol. Chem. 273, 2926–2930 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Gross, A., McDonnell, J.M. & Korsmeyer, S.J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Wei, M.C. et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14, 2060–2071 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Varfolomeev, E.E. et al. Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267–276 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Yeh, W.C. et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279, 1954–1958 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, J., Cado, D., Chen, A., Kabra, N.H. & Winoto, A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296–300 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Yeh, W.C. et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12, 633–642 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Bergeron, L. et al. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev. 12, 1304–1314 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Newton, K., Harris, A.W., Bath, M.L., Smith, K.G.C. & Strasser, A. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17, 706–718 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Newton, K., Harris, A.W. & Strasser, A. FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. EMBO J. 19, 931–941 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, H., Zhu, H., Xu, C.J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Gross, A. et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J. Biol. Chem. 274, 1156–1163 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Yin, X.M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400, 886–891 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Watanabe-Fukunaga, R., Brannan, C.I., Copeland, N.G., Jenkins, N.A. & Nagata, S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356, 314–317 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Novack, D.V. & Korsmeyer, S.J. Bcl-2 protein expression during murine development [see comments]. Am. J. Pathol. 145, 61–73 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Merry, D.E., Veis, D.J., Hickey, W.F. & Korsmeyer, S.J. bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS. Development 120, 301–311 (1994).

    CAS  PubMed  Google Scholar 

  24. Veis, D.J., Sorenson, C.M., Shutter, J.R. & Korsmeyer, S.J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75, 229–240 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Gonzalez-Garcia, M. et al. bcl-XL is the major bcl-x mRNA form expressed during murine development and its product localizes to mitochondria. Development 120, 3033–3042 (1994).

    CAS  PubMed  Google Scholar 

  26. Motoyama, N. et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267, 1506–1510 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Ma, A. et al. Bclx regulates the survival of double-positive thymocytes. Proc. Natl. Acad. Sci. USA 92, 4763–4767 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Print, C.G. et al. Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc. Natl. Acad. Sci. USA 95, 12424–12431 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ross, A.J. et al. Testicular degeneration in Bclw-deficient mice [see comments]. Nature Genet . 18, 251–256 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Rinkenberger, J.L., Horning, S., Klocke, B., Roth, K. & Korsmeyer, S.J. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev. 14, 23–27 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhou, P. et al. Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 92, 3226–3239 (1998).

    CAS  PubMed  Google Scholar 

  32. Hamasaki, A. et al. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J. Exp. Med. 188, 1985–1992 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Knudson, C.M., Tung, K.S., Tourtellotte, W.G., Brown, G.A. & Korsmeyer, S.J. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96–99 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Knudson, C.M. & Korsmeyer, S.J. Bcl-2 and Bax function independently to regulate cell death. Nature Genet. 16, 358–363 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. White, F.A., Keller-Peck, C.R., Knudson, C.M., Korsmeyer, S.J. & Snider, W.D. Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J. Neurosci. 18, 1428–1439 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Deckwerth, T.L. et al. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17, 401–411 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Miller, T.M. et al. Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. J. Cell Biol. 139, 205–217 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Perez, G.I. et al. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nature Genet. 21, 200–203 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Lindsten, T. et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol. Cell 6, 1389–1399 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wei, M. et al. Pro-apoptotic BAX and BAK are a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Li, K. et al. Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101, 389–399 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Susin, S.A. et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Coucouvanis, E. & Martin, G.R. Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo. Cell 83, 279–287 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Joza, N. et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410, 549–554 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Deveraux, Q.L. & Reed, J.C. IAP family proteins—suppressors of apoptosis. Genes Dev 13, 239–252 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Verhagen, A.M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Woo, M. et al. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12, 806–819 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Cecconi, F., Alvarez-Bolado, G., Meyer, B.I., Roth, K.A. & Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Yoshida, H. et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94, 739–750 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Zheng, T.S. et al. Caspase-3 controls both cytoplasmic and nuclear events associated with Fas-mediated apoptosis in vivo. Proc. Natl. Acad. Sci. USA 95, 13618–13623 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zheng, T.S. et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nature Med. 6, 1241–1247 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Woo, M. et al. In vivo evidence that caspase-3 is required for Fas-mediated apoptosis of hepatocytes. J. Immunol. 163, 4909–4916 (1999).

    CAS  PubMed  Google Scholar 

  59. Li, P. et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 80, 401–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267, 2000–2003 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Kang, S.J. et al. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 149, 613–622 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schielke, G.P., Yang, G.Y., Shivers, B.D. & Betz, A.L. Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J. Cereb. Blood Flow Metab. 18, 180–185 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Honarpour, N. et al. Adult Apaf-1-deficient mice exhibit male infertility. Dev. Biol. 218, 248–258 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Michaelidis, T.M. et al. Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17, 75–89 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank E. Smith for illustrations and for his assistance in preparing the manuscript.

Author information

Authors and Affiliations

  1. Department of Pathology and Medicine, Howard Hughes Medical Institute, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Ann M. Ranger, Barbara A. Malynn & Stanley J. Korsmeyer

Authors
  1. Ann M. Ranger
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Barbara A. Malynn
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Stanley J. Korsmeyer
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Stanley J. Korsmeyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ranger, A., Malynn, B. & Korsmeyer, S. Mouse models of cell death. Nat Genet 28, 113–118 (2001). https://doi.org/10.1038/88815

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/88815

This article is cited by

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