Defects in regulation of apoptosis in caspase-2-deficient mice

  1. Louise Bergeron,
  2. Gloria I. Perez,
  3. Glen Macdonald,
  4. Lianfa Shi,
  5. Yi Sun,
  6. Andrea Jurisicova,
  7. Sue Varmuza,
  8. Keith E. Latham,
  9. Jodi A. Flaws,
  10. Jessica C.M. Salter,
  11. Hideaki Hara,
  12. Michael A. Moskowitz,
  13. En Li,
  14. Arnold Greenberg,
  15. Jonathan L. Tilly, and
  16. Junying Yuan
  1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 USA; The Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114 USA; Manitoba Institute of Cell Biology, Manitoba Cancer Treatment and Research Foundation, University of Manitoba, Winnipeg, Manitoba, Canada R3E OV9; Division of Neuroscience, Department of Neurology, Children’s Hospital, Boston, Massachusetts 02115 USA; Departments of Zoology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada M5S 3G5; Fels Institute for Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 USA; Department of Anatomy, University of Maryland School of Medicine, Baltimore, Maryland 21201 USA; Stroke and Neurovascular Regulation, Neurosurgical Service, Departments of Surgery and Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129 USA; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129 USA

Abstract

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.

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Footnotes

  • Corresponding author.

  • E-MAIL jyuan{at}hms.harvard.edu; FAX (617) 432-4177.

    • Received January 3, 1998.
    • Accepted March 6, 1998.
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