Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice (original) (raw)

Nature volume 384, pages 368–372 (1996)Cite this article

Abstract

PROGRAMMED cell death (apoptosis) is a prominent feature of the development of the immune and nervous systems1,2. The identification of the Caenorhabditis elegans cell death gene, ced-3, as a prototype of the interleukin-lβ converting enzyme (ICE) protease family has led to extensive evidence implicating these enzymes in apoptosis3,4. Among the ten or more members of the ICE protease family, CPP32/yama/apopain5–7 exhibits the highest similarity to CED-3 in both sequence homology and substrate specificity8. To analyse its function in vivo, we generated CPP32-deficient mice by homologous recombination. These mice, born at a frequency lower than expected by mendelian genetics, were smaller than their littermates and died at 1–3 weeks of age. Although their thymocytes retained normal susceptibility to various apoptotic stimuli, brain development in CPP32-deficient mice was profoundly affected, and discernible by embryonic day 12, resulting in a variety of hyperplasias and disorganized cell deployment. These supernumerary cells were postmitotic and terminally differentiated by the postnatal stage. Pyknotic clusters at sites of major morphogenetic change during normal brain development9 were not observed in the mutant embryos, indicating decreased apoptosis in the absence of CPP32. Thus CPP32 is shown to play a critical role during morphogenetic cell death9,10 in the mammalian brain.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Osborne, B. A. Curr. Opin. Immunol. 8, 245–254 (1996).
    Article CAS Google Scholar
  2. Oppenheim, R. W. Annu. Rev. Nuerosci. 14, 453–501 (1991).
    Article CAS Google Scholar
  3. Whyte, M. Trends Cell Biol. 6, 245–248 (1996).
    Article CAS Google Scholar
  4. Kuida, K. et al. Science 267, 2000–2003 (1995).
    Article ADS CAS Google Scholar
  5. Fernandes-Alnemri, T. et al. J. Biol. Chem. 269, 30761–30764 (1994).
    CAS PubMed Google Scholar
  6. Tewari, M. et al. Cell 81, 801–809 (1995).
    Article CAS Google Scholar
  7. Nicholson, D. W. et al. Nature 376, 37–43 (1995).
    Article ADS CAS Google Scholar
  8. Xue, D., Shaham, S. & Horvitz, H. R. Genes Dev. 10, 1073–1083 (1996).
    Article CAS Google Scholar
  9. Kallen, B. J. Anat. 89, 153–161 (1955).
    CAS PubMed PubMed Central Google Scholar
  10. Glucksmann, A. Biol. Rev. 26, 59–86 (1951).
    Article CAS Google Scholar
  11. Fernandes-Alnemri, T. et al. Cancer Res. 55, 2737–2742 (1995).
    CAS Google Scholar
  12. Fernandes-Alnemri, T. et al. Cancer Res. 55, 6045–6052 (1995).
    CAS PubMed Google Scholar
  13. Lippke, J. A. et al. J. Biol. Chem. 271, 1825–1828 (1996).
    Article CAS Google Scholar
  14. Eksioglu, Y. Z. et al. Neuron 16, 77–87 (1996).
    Article CAS Google Scholar
  15. Miale, I. L. & Sidman, R. L. Exp. Neurol. 4, 277–296 (1961).
    Article CAS Google Scholar
  16. Rakic, P. J. Comp. Neurol. 141, 283–312 (1971).
    Article CAS Google Scholar
  17. Kerr, J. F. R., Wyllie, A. H. & Currie, A. R. Br. J. Cancer 26, 239–257 (1972).
    Article CAS Google Scholar
  18. Homma, S., Yaginuma, H. & Oppenheim, R. W. J. Comp. Neurol. 345, 377–395 (1994).
    Article CAS Google Scholar
  19. Silver, J. & Hughes, A. F. W. J. Morphol. 140, 159–170 (1973).
    Article CAS Google Scholar
  20. Rakic, P. & Yakovlev, P. I. J. Comp. Neurol. 132, 45–72 (1968).
    Article CAS Google Scholar
  21. Ellis, H. & Horvitz, H. R. Cell 44, 817–829 (1986).
    Article CAS Google Scholar
  22. Horvitz, H. R. et al. Cold Spring Harb. Symp. Quant. Biol. 48, 453–463 (1983).
    Article Google Scholar
  23. Chinnaiyan, A. & Dixit, V. Curr. Biol. 6, 555–562 (1996).
    Article CAS Google Scholar
  24. Hamburger, V. Am. J. Anat. 102, 265–402 (1958).
    Article Google Scholar
  25. Cowan, W. M. et al. Science 225, 1258–1265 (1984).
    Article ADS CAS Google Scholar
  26. Pittman, R. & Oppenheim, R. W. J. Comp. Neurol. 187, 425–446 (1979).
    Article CAS Google Scholar
  27. Wang, X. et al. EMBO J. 15, 1012–1020 (1996).
    Article CAS Google Scholar
  28. Martin, S. J. et al. J. Exp. Med. 182, 1545–1556 (1995).
    Article CAS Google Scholar
  29. Vermes, I. et al. J. Immunol. Methods 184, 39–51 (1995).
    Article CAS Google Scholar
  30. Miller, M. W. & Nowakoski, R. S. Brain Res. 457, 44–52 (1988).
    Article CAS Google Scholar

Download references

Author information

Authors and Affiliations

  1. Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut, 06510, USA
    Keisuke Kuida, Timothy S. Zheng, Songqing Na, Di Yang & Richard A. Flavell
  2. Section of Neurobiology, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut, 06510, USA
    Chia-Yi Kuan & Pasko Rakic
  3. Department of Immunology, Tokyo Metropolitan Institute of Medicine Science, 3-18-22 Hon-Komagome, BunKyo-Ku, Tokyo, 113, Japan
    Keisuke Kuida & Hajime Karasuyama

Authors

  1. Keisuke Kuida
    You can also search for this author inPubMed Google Scholar
  2. Timothy S. Zheng
    You can also search for this author inPubMed Google Scholar
  3. Songqing Na
    You can also search for this author inPubMed Google Scholar
  4. Chia-Yi Kuan
    You can also search for this author inPubMed Google Scholar
  5. Di Yang
    You can also search for this author inPubMed Google Scholar
  6. Hajime Karasuyama
    You can also search for this author inPubMed Google Scholar
  7. Pasko Rakic
    You can also search for this author inPubMed Google Scholar
  8. Richard A. Flavell
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Kuida, K., Zheng, T., Na, S. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice.Nature 384, 368–372 (1996). https://doi.org/10.1038/384368a0

Download citation