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Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells

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Abstract

Previously, we analyzed mice lacking either caspase-2 or caspase-3 and documented a role for caspase-2 in developmental and chemotherapy-induced apoptosis of oocytes. Those data also revealed dispensability of caspase-3, although we found this caspase critical for ovarian granulosa cell death. Because of the mutual interdependence of germ cells and granulosa cells, herein we generated caspase-2 and -3 double-mutant (DKO) mice to evaluate how these two caspases functionally relate to each other in orchestrating oocyte apoptosis. No difference was observed in the rate of spontaneous oocyte apoptosis between DKO and wildtype (WT) females. In contrast, the oocytes from DKO females were more susceptible to apoptosis induced by DNA damaging agents, compared with oocytes from WT females. This increased sensitivity to death of DKO oocytes appears to be a specific response to DNA damage, and it was associated with a compensatory upregulation of caspase-12. Interestingly, DKO oocytes were more resistant to apoptosis induced by methotrexate (MTX) than WT oocytes. These results revealed that in female germ cells, insults that directly interfere with their metabolic status (e.g. MTX) require caspase-2 and caspase-3 as obligatory executioners of the ensuing cell death cascade. However, when DNA damage is involved, and in the absence of caspase-2 and -3, caspase-12 becomes upregulated and mediates apoptosis in oocytes.

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Abbreviations

BSA:

bovine serum albumin

DKO:

double knockout

DXR:

doxorubicin

eCG:

equine chorionic gonadotropin

ER:

endoplasmic reticulum

hCG:

human chorionic gonadotropin

HTF:

human tubal fluid

LPS:

bacterial lipopolysaccharide

MTX:

methotrexate

PCD:

programmed cell death

WT:

wildtype

z-VAD:

pancaspase inhibitor

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Acknowledgments

Supported by the Department of Physiology Michigan State University (GIP), and Vincent Research Funds, Massachusetts General Hospital (GIP). During these studies the following research fellows were supported by various institutions: Y Takai by the Department of OB/GYN, University of Tokyo, Faculty of Medicine (Tokyo, Japan); T Matikainen by the Finnish Foundation for Pediatric Research and the Finnish Cultural Foundation; A Jurisicova was supported by a New Investigator Salary Award from the Canadian Institutes of Health Research; MR Kim by the Department of OB/GYN, The Catholic University of Korea (Seoul, Korea). We would like to thank Mr. Sam Riley (Photo Lab, MGH) for outstanding assistance with the preparation of figures and image analysis.

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Authors and Affiliations

  1. Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 02114, USA

    Y. Takai, T. Matikainen, M. R. Kim, A. M. Trbovich & J. L. Tilly

  2. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada

    A. Jurisicova

  3. Divisions of Development and Differentiation, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan

    E. Fujita & T. Momoi

  4. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    T. Nakagawa & J. Yuan

  5. Division of Cellular and Molecular Biology, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Ontario, Canada

    B. Lemmers & R. Hakem

  6. Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06510, USA

    R. A. Flavell

  7. Department of Physiology, Michigan State University, 4173 BPS, East Lansing, Michigan, 48824, USA

    G. I. Perez

Authors
  1. Y. Takai
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  2. T. Matikainen
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  3. A. Jurisicova
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  4. M. R. Kim
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  5. A. M. Trbovich
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  6. E. Fujita
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  7. T. Nakagawa
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  8. B. Lemmers
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  9. R. A. Flavell
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  10. R. Hakem
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  11. T. Momoi
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  12. J. Yuan
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  13. J. L. Tilly
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  14. G. I. Perez
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Corresponding author

Correspondence to G. I. Perez.

Additional information

Takai and Matikainen contributed equally to this work.

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Takai, Y., Matikainen, T., Jurisicova, A. et al. Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells. Apoptosis 12, 791–800 (2007). https://doi.org/10.1007/s10495-006-0022-z

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  • DOI: https://doi.org/10.1007/s10495-006-0022-z

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