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.

  • Review Article
  • Published:

Commuting the death sentence: how oocytes strive to survive

Nature Reviews Molecular Cell Biology volume 2, pages 838–848 (2001)Cite this article

Key Points

  • Programmed cell death (apoptosis) claims up to 99.9% of the cells in the mammalian female germ line, which drives irreversible infertility, ovarian failure and the menopause in humans.

  • Exciting insights into the mechanisms that underlie germ-cell apoptosis have recently been provided by the study of oocyte death in lower organisms and in genetically manipulated mice that lack apoptosis-regulatory proteins.

  • Results from these investigations have already affected many aspects of biology and medicine - from advances in our understanding of mitochondrial inheritance and function in embryonic development to therapeutic approaches to preserve fertility and delay menopause. Furthermore, new cell death-signalling pathways have been uncovered from studies of female germ-cell death that have opened new research opportunities of broad scientific interest.

  • However, many questions remained unanswered, and the reasons why the female body creates, only to delete, so many germ cells are still a mystery. This review summarizes what is known about the occurrence, regulation and functions of programmed cell death in the female germ line during embryonic and post-natal life, and how this information is being used for therapeutic purposes to try to combat infertility and the ageing process.

Abstract

Programmed cell death claims up to 99.9% of the cells in the mammalian female germ line, which eventually drives irreversible infertility and ovarian failure — the menopause in humans. New insights into the mechanisms that underlie germ-cell apoptosis have been provided by the study of oocyte death in lower organisms and in genetically manipulated mice that lack apoptosis-regulatory proteins. With new therapeutic tools to control fertility, oocyte quality and ovarian lifespan on the horizon, understanding how and why the female body creates, only to delete, so many germ cells is imperative.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Hypotheses to explain mammalian fetal ovarian germline death.
Figure 2: Evolutionary conservation of the regulation of apoptosis.
Figure 3: The sphingomyelin pathway and fertility preservation.
Figure 4: Mechanism of Ahr action.
Figure 5: Use of a xenograft model to study human primordial oocyte function in vivo.

Similar content being viewed by others

References

  1. Flemming, W. Über die bildung von richtungsfiguren in säugethiereiern beim untergang Graaf'scher follikel. Archiv fur Anatomie und Entwickelungsgeschichte (Archiv. Anat. Physiol.) 221–244 (1885).

  2. Kerr, J. F. R., 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Tilly, J. L., Kowalski, K. I., Johnson, A. L. & Hsueh, A. J. W. Involvement of apoptosis in ovarian follicular atresia and postovulatory regression. Endocrinology 129, 2799–2801 (1991).

    CAS  PubMed  Google Scholar 

  4. Hughes, F. M. Jr & Gorospe, W. C. Biochemical identification of apoptosis (programmed cell death) in granulosa cells: evidence for a potential mechanism underlying follicular atresia. Endocrinology 129, 2415–2422 (1991).

    CAS  PubMed  Google Scholar 

  5. Gross, A., McDonnell, J. M. & Korsmeyer, S. J. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999).A superlative review of the Bcl-2 gene family and apoptosis, with particular emphasis on the role of mitochondria as both molecular targets and central executioners in programmed cell death.

    Article  CAS  PubMed  Google Scholar 

  6. Budihardjo, I., Oliver, H., Lutter, M., Luo, X. & Wang, X. Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol. 15, 269–290 (1999).

    CAS  PubMed  Google Scholar 

  7. Reed, J. C. Mechanisms of apoptosis. Am. J. Pathol. 157, 1415–1430 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ranger, A. M., Malynn, B. A. & Korsmeyer, S. J. Mouse models of cell death. Nature Genet. 28, 113–118 (2001).

    CAS  PubMed  Google Scholar 

  9. Adrain, C. & Martin, S. J. The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem. Sci. 26, 390–397 (2001).

    CAS  PubMed  Google Scholar 

  10. Shi, Y. A structural view of mitochondria-mediated apoptosis. Nature Struct. Biol. 8, 394–401 (2001).A thorough and up-to-date overview of the cell and molecular biology of apoptosis and its control in both vertebrate and invertebrate animal species, with detailed discussions of how several key protein families act and interact to determine cell fate.

    CAS  PubMed  Google Scholar 

  11. Morita, Y. & Tilly, J. L. Oocyte apoptosis: like sand through an hourglass. Dev. Biol. 213, 1–17 (1999).

    CAS  PubMed  Google Scholar 

  12. Buehr, M. The primordial germ cells of mammals: some current perspectives. Exp. Cell Res. 232, 194–207 (1997).

    CAS  PubMed  Google Scholar 

  13. Briggs, D., Miller, D. & Gosden, R. G. in Molecular Biology in Reproductive Medicine (ed. Fauser, B. C. J. M.) 251–269 (Parthenon, New York, 1999).

    Google Scholar 

  14. Baker, T. G. A quantitative and cytological study of germ cells in human ovaries. Proc. R. Soc. Lond. B 158, 417–433 (1963).

    CAS  PubMed  Google Scholar 

  15. Beaumont, H. M. & Mandl, A. M. A quantitative and cytological study of oogonia and oocytes in the foetal and neonatal rat. Proc. R. Soc. Lond. B 155, 557–579 (1961).

    Google Scholar 

  16. Giehl, K. M. Trophic dependencies of rodent corticospinal neurons. Rev. Neurosci. 12, 79–94 (2001).

    CAS  PubMed  Google Scholar 

  17. Jacobson, M. D., Weil, M. & Raff, M. C. Programmed cell death in animal development. Cell 88, 347–354 (1997).

    CAS  PubMed  Google Scholar 

  18. Mintz, B. & Russell, E. S. Gene-induced embryological modification of primordial germ cells in the mouse. J. Exp. Zool. 134, 207–230 (1957).

    CAS  PubMed  Google Scholar 

  19. Morita, Y. et al. Caspase-2 deficiency rescues female germ cells from death due to cytokine insufficiency but not meiotic defects caused by ataxia telangiectasia-mutated (Atm) gene inactivation. Cell Death Differ. 8, 614–620 (2001).

    CAS  PubMed  Google Scholar 

  20. Morita, Y. et al. Requirement for phosphatidylinositol-3'-kinase in cytokine-mediated germ cell survival during fetal oogenesis in the mouse. Endocrinology 140, 941–949 (1999).

    CAS  PubMed  Google Scholar 

  21. Morita, Y. et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nature Med. 6, 1109–1114 (2000).This identifies the sphingomyelin pathway as a key regulator of female germline death, and shows that sphingosine-1-phosphate, an inhibitor of ceramide-promoted apoptosis, preserves ovarian function and fertility in adult female mice that were exposed to anti-cancer therapy in vivo.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Barlow, C. et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125, 4007–4017 (1998).

    CAS  PubMed  Google Scholar 

  24. Burgoyne, P. S. & Baker, T. G. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J. Reprod. Fertil. 75, 633–645 (1985).

    CAS  PubMed  Google Scholar 

  25. Zinn, A. R. & Ross, J. L. Turner syndrome and haploinsufficiency. Curr. Opin. Genet. Dev. 8, 322–327 (1998).

    CAS  PubMed  Google Scholar 

  26. Speed, R. M. The possible role of meiotic pairing anomalies in the atresia of human fetal oocytes. Hum. Genet. 78, 260–266 (1988).

    CAS  PubMed  Google Scholar 

  27. Mittwoch, U. & Mahadevaiah, S. K. Unpaired chromosomes at meiosis: cause or effect of gametogenic insufficiency? Cytogenet. Cell Genet. 59, 274–279 (1992).

    CAS  PubMed  Google Scholar 

  28. Pepling, M. E., de Cuevas, M. & Spradling, A. C. Germline cysts: a conserved phase of germ cell development? Trends Cell Biol. 9, 257–262 (1999).

    CAS  PubMed  Google Scholar 

  29. Pepling, M. E. & Spradling, A. C. Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. Dev. Biol. 234, 339–351 (2001).An interesting exploration into the possible functions of germline cyst formation and breakdown in mammalian oogenesis.

    CAS  PubMed  Google Scholar 

  30. de Cuevas, M., Lilly, M. A. & Spradling, A. C. Germline cyst formation in Drosophila. Annu. Rev. Genet. 31, 405–428 (1997).

    CAS  PubMed  Google Scholar 

  31. Tittel, J. N. & Steller, H. A comparison of programmed cell death between species. Genome Biol. 1, 1–3 (2000). | PubMed |

    Google Scholar 

  32. Foley, K. & Cooley, L. Apoptosis in late stage Drosophila nurse cells does not require genes within the H99 deficiency. Development 125, 1075–1082 (1998).

    CAS  PubMed  Google Scholar 

  33. McCall, K. & Steller, H. Requirement for DCP-1 caspase during Drosophila oogenesis. Science 279, 230–234 (1998).

    CAS  PubMed  Google Scholar 

  34. Gumienny, T. L., Lambie, E., Hartweig, 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 

  35. Liu, Q. A. & Hengartner, M. O. The molecular mechanism of programmed cell death in C. elegans. Ann. N. Y. Acad. Sci. 887, 92–104 (1999).

    CAS  PubMed  Google Scholar 

  36. Krakauer, D. C. & Mira, A. Mitochondria and germ-cell death. Nature 400, 125–126 (1999).

    CAS  PubMed  Google Scholar 

  37. Perez, G. I., Trbovich, A. M., Gosden, R. G. & Tilly, J. L. Mitochondria and the death of oocytes. Nature 403, 500–501 (2000).

    CAS  PubMed  Google Scholar 

  38. Faddy, M. J., Gosden, R. G., Gougeon, A., Richardson, S. J. & Nelson, J. F. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum. Reprod. 7, 1342–1346 (1992).

    CAS  PubMed  Google Scholar 

  39. Richardson, S. J., Senikas, V. & Nelson, J. F. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J. Clin. Endocrinol. Metab. 65, 1231–1237 (1987).

    CAS  PubMed  Google Scholar 

  40. Gosden, R. G., Laing, S. C., Felicio, L. S., Nelson, J. F. & Finch, C. E. Imminent oocyte exhaustion and reduced follicular recruitment mark the transition to acyclicity in aging C57BL/6J mice. Biol. Reprod. 28, 255–260 (1983).

    CAS  PubMed  Google Scholar 

  41. Pru, J. K. & Tilly, J. L. Programmed cell death in the ovary: insights and future prospects using genetic technologies. Mol. Endocrinol. 15, 845–853 (2001).

    CAS  PubMed  Google Scholar 

  42. Perez, G. I. et al. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nature Genet. 21, 200–203 (1999).This shows that Bax is a required mediator of oocyte depletion in postnatal life, and shows for the first time that attenuating the rate of oocyte loss can prolong ovarian lifespan and therefore prevent the mouse equivalent of menopause in aged animals.

    CAS  PubMed  Google Scholar 

  43. Palacios, S. Current perspectives on the benefits of HRT in menopausal women. Maturitas 33, S1–S13 (1999).

    CAS  PubMed  Google Scholar 

  44. Kenemans, P., van Unnik, G. A., Mijatovic, V. & van der Morren, M. J. Perspectives in hormone replacement therapy. Maturitas 38, S41–S48 (2001).

    CAS  PubMed  Google Scholar 

  45. Beral, V., Banks, E., Reeves, G. & Appleby, P. Use of HRT and the subsequent risk of cancer. J. Epidemiol. Biostat. 4, 191–210 (1999).

    CAS  PubMed  Google Scholar 

  46. Von Saal, F. S., Finch, C. E. & Nelson, J. F. in Physiology of Reproduction (eds Knobil, E. et al.) 2351–2431 (Raven, New York, 1988).

    Google Scholar 

  47. Pantos, K. et al. Influence of advanced age on the blastocyst development rate and pregnancy rate in assisted reproductive technology. Fertil. Steril. 71, 1144–1146 (1999).

    CAS  PubMed  Google Scholar 

  48. Rosenwaks, Z., Davis, O. K. & Damario, M. A. The role of maternal age in assisted reproduction. Hum. Reprod. Suppl. 10, 165–172 (1995). | PubMed |

    Google Scholar 

  49. Van Kooji, R. J., Looman, C. W. N., Habbema, J. D. F., Dorland, M. & te Velde, E. Age-dependent decrease in embryo implantation rate after in vitro fertilization. Fertil. Steril. 66, 769–775 (1996).

    Google Scholar 

  50. Navot, D. et al. Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation. Fertil. Steril. 61, 97–101 (1994).

    CAS  PubMed  Google Scholar 

  51. Balmaceda, J. P. et al. Oocyte donation in humans: a model to study the effect of age on embryo implantation rate. Hum. Reprod. 9, 2160–2163 (1994).

    CAS  PubMed  Google Scholar 

  52. Ziebe, S. et al. Embryo quality and developmental potential is compromised by age. Acta Obstet. Gynecol. Scand. 80, 169–174 (2001).

    CAS  PubMed  Google Scholar 

  53. Henderson, S. A. & Edwards, R. G. Chiasma frequency and maternal age in mammals. Nature 217, 22–28 (1968).

    Google Scholar 

  54. Speed, R. M. & Chandley, A. C. Meiosis in the foetal mouse ovary. II. Oocyte development and age-related aneuploidy. Does a production line exist? Chromosoma 88, 184–189 (1983).

    CAS  PubMed  Google Scholar 

  55. Beermann, F., Bartels, I., Franke, U. & Hansmann, I. Chromosome segregation at meiosis I in female T(2;4)1Go/+ mice: no evidence for a decreased crossover frequency with maternal age. Chromosoma 96, 1–7 (1987).

    Google Scholar 

  56. Paulson, R. J., Thornton, M. H., Francis, M. M. & Salvador, H. S. Successful pregnancy in a 63-year-old woman. Fertil. Steril. 67, 949–951 (1997).

    CAS  PubMed  Google Scholar 

  57. Spandorfer, S. D. et al. An analysis of the effect of age on implantation rates. J. Assist. Reprod. Genet. 17, 303–306 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Antczak, M. & Van Blerkom, J. Temporal and spatial aspects of fragmentation in early human embryos: possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains. Hum. Reprod. 14, 429–447 (1999).

    CAS  PubMed  Google Scholar 

  59. Ziebe, S. et al. Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization. Hum. Reprod. 12, 1545–1549 (1997).

    CAS  PubMed  Google Scholar 

  60. Jurisicova, A., Varmuza, S. & Casper, R. F. Programmed cell death and human embryo fragmentation. Mol. Hum. Reprod. 2, 93–98 (1996).

    CAS  PubMed  Google Scholar 

  61. Levy, R., Benchaib, M., Cordonier, H., Souchier, C. & Guerin, J. Annexin-V labelling and terminal transferase-mediated DNA end-labeling (TUNEL) assay in human arrested embryos. Mol. Hum. Reprod. 4, 775–783 (1998).

    CAS  PubMed  Google Scholar 

  62. Cohen, J. et al. Ooplasmic transfer in mature human oocytes. Mol. Hum. Reprod. 4, 269–280 (1998).

    CAS  PubMed  Google Scholar 

  63. Jurisicova, A. et al. Mitochondrial function and behaviour in mammalian oocytes and during preimplantation embryo development. J. Soc. Gynecol. Invest. 8, 49A (2001).

    Google Scholar 

  64. Brenner, C. A., Barritt, J. A., Willadsen, S. & Cohen, J. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation. Fertil. Steril. 74, 573–578 (2000).

    CAS  PubMed  Google Scholar 

  65. Waxman, J. Chemotherapy and the adult gonad: a review. J. R. Soc. Med. 76, 144–148 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ried, H. L. & Jaffe, N. Radiation-induced changes in long-term survivors of childhood cancer after treatment with radiation therapy. Semin Roentgenol 29, 6–14 (1994).

    CAS  PubMed  Google Scholar 

  67. Greenlee, R. T., Murray, T., Bolden, S. & Wingo, P. A. Cancer statistics, 2000. CA Cancer J. Clin. 50, 7–33 (2000).

    CAS  PubMed  Google Scholar 

  68. Perez, G. I., Knudson, C. M., Leykin, L., Korsmeyer, S. J. & Tilly, J. L. Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction. Nature Med. 3, 1228–1332 (1997).This identifies apoptosis as the mechanism by which female germ cells degenerate in response to anti-cancer therapy, and delineates several key steps in the programmed-cell-death-signalling pathway that are required for chemotherapeutic drugs to kill oocytes.

    CAS  PubMed  Google Scholar 

  69. Reynolds, T. Cell death genes may hold clues to preserving fertility after chemotherapy. J. Natl Cancer Inst. 91, 664–666 (1999).

    CAS  PubMed  Google Scholar 

  70. Morita, Y., Perez, G. I., Maravei, D. V., Tilly, K. I. & Tilly, J. L. Targeted expression of Bcl-2 in mouse oocytes inhibits ovarian follicle atresia and prevents spontaneous and chemotherapy-induced oocyte apoptosis in vitro. Mol. Endocrinol. 13, 841–850 (1999).

    CAS  PubMed  Google Scholar 

  71. Xiang, J., Chao, D. T. & Korsmeyer, S. J. BAX-induced cell death may not require interleukin-1β-converting enzyme-like proteases. Proc. Natl Acad. Sci. USA 93, 14559–14563 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kolesnick, R. N. & Kronke, M. Regulation of ceramide production and apoptosis. Annu. Rev. Physiol. 60, 643–665 (1998).

    CAS  PubMed  Google Scholar 

  73. Cremesti, A. et al. Ceramide enables Fas to cap and kill. J. Biol. Chem. 276, 23954–23961 (2001).

    CAS  PubMed  Google Scholar 

  74. Pastorino, J. G. et al. Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J. Biol. Chem. 274, 31734–31739 (1999).

    CAS  PubMed  Google Scholar 

  75. Cuvillier, O. et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803 (1996).

    CAS  PubMed  Google Scholar 

  76. Spiegel, S. et al. Sphingosine-1-phosphate in cell growth and death. Ann. N. Y. Acad. Sci. 845, 11–18 (1998).

    CAS  PubMed  Google Scholar 

  77. Paris, F., Perez, G. I., Kolesnick, R. N. & Tilly, J. L. Suppression of oocyte apoptosis by sphingosine-1-phosphate therapy in vivo preserves fertility following radiotherapy. Proc. 83rd Annu. Meeting Endocrine Soc., Denver, CO 374 (2001).

  78. Jick, H. & Porter, J. Relation between smoking and age of natural menopause. Report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet 1, 1354–1355 (1977).

    CAS  PubMed  Google Scholar 

  79. Mattison, D. R. et al. The effect of smoking on oogenesis, fertilization and implantation. Sem. Reprod. Health 7, 291–304 (1989).

    Google Scholar 

  80. Sharara, F. I., Beatse, S. N., Leonardi, M. R., Navot, D. & Scott, R. T. Jr Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by the clomiphene citrate challenge test. Fertil. Steril. 62, 257–262 (1994).

    CAS  PubMed  Google Scholar 

  81. Weinberg, C. R., Wilcox, A. J. & Baird, D. D. Reduced fecundability in women with prenatal exposure to cigarette smoking. Am. J. Epidemiol. 129, 1072–1078 (1989).

    CAS  PubMed  Google Scholar 

  82. Hoffmann, D. & Hoffmann, I. The changing cigarette, 1950–1995. J. Toxicol. Environ. Health 50, 307–364 (1997).

    CAS  PubMed  Google Scholar 

  83. Bolon, B. et al. Differential follicle counts as a screen for chemically induced ovarian toxicity in mice: results from continuous breeding bioassays. Fundam. Appl. Toxicol. 39, 1–10 (1997).

    CAS  PubMed  Google Scholar 

  84. Bucci, T. J., Bolon, B., Warbritton, A. R., Chen, J. J. & Heindel, J. J. Influence of sampling on the reproducibility of ovarian follicle counts in mouse toxicity studies. Reprod. Toxicol. 11, 689–696 (1997).

    CAS  PubMed  Google Scholar 

  85. Mattison, D. R. & Thorgeirsson, S. S. Genetic differences in mouse ovarian metabolism of benzo[a]pyrene and oocyte toxicity. Biochem. Pharmacol. 26, 909–912 (1977).

    CAS  PubMed  Google Scholar 

  86. Mackenzie, K. M. & Angevine, D. M. Infertility in mice exposed in utero to benzo(a)pyrene. Biol. Reprod. 24, 183–191 (1981).

    CAS  PubMed  Google Scholar 

  87. Vahakangas, K., Rajaniemi, H. & Pelkonen, O. Ovarian toxicity of cigarette smoke exposure during pregnancy in mice. Toxicol. Lett. 25, 75–80 (1985).

    CAS  PubMed  Google Scholar 

  88. Hankinson, O. The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol. 35, 307–340 (1995).

    CAS  PubMed  Google Scholar 

  89. Robles, R. et al. The aryl hydrocarbon receptor, a basic helix–loop–helix transcription factor of the PAS gene family, is required for normal ovarian germ cell dynamics in the mouse. Endocrinology 141, 450–453 (2000).

    CAS  PubMed  Google Scholar 

  90. Hahn, M. E. The aryl hydrocarbon receptor: a comparative perspective. Comp. Biochem. Physiol. C. 121, 23–53 (1998).

    CAS  PubMed  Google Scholar 

  91. Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722–726 (1995).

    CAS  PubMed  Google Scholar 

  92. Schmidt, J. V., Su, G. H., Reddy, J. K., Simon, M. C. & Bradfield, C. A. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc. Natl Acad. Sci. USA 93, 6731–6736 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Matikainen, T. et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nature Genet. 28, 355–360 (2001).

    CAS  PubMed  Google Scholar 

  94. Matikainen, T. et al. Ligand activation of the aromatic hydrocarbon receptor (AHR)-transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology (in the press).References 93 and 94 describe the discovery of a new cell-death-signalling pathway, and the role of this pathway in mediating oocyte loss following exposure of the ovaries to a ubiquitous class of toxic environmental chemicals.

  95. Darwin, C. The Evolution of the Species (Appleton, New York, 1860).

    Google Scholar 

  96. Dunkel, L., Hirvonen, V. & Erkkilä, K. Clinical aspects of male germ cell apoptosis during testis development and spermatogenesis. Cell Death Differ. 4, 171–179 (1997).

    CAS  PubMed  Google Scholar 

  97. Weissman, A. et al. Preliminary experience with subcutaneous human ovarian cortex transplantation in the NOD-SCID mouse. Biol. Reprod. 60, 1462–1467 (1999).

    CAS  PubMed  Google Scholar 

  98. Jansen, R. P. & de Boer, K. The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate. Mol. Cell. Endocrinol. 145, 81–88 (1998).An insightful perspective on mitochondrial replication during oogenesis, and on how integrity of the mitochondrial genome is ensured from one generation to the next.

    CAS  PubMed  Google Scholar 

  99. Cummins, J. M. Fertilization and elimination of the paternal mitochondrial genome. Hum. Reprod. 15, 92–101 (2000).

    PubMed  Google Scholar 

  100. Lynch, M. Mutation accumulation in transfer RNAs: molecular evidence for Muller's ratchet in mitochondrial genomes. Mol. Biol. Evol. 13, 209–220 (1996).

    CAS  PubMed  Google Scholar 

  101. Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992).

    CAS  PubMed  Google Scholar 

  102. Barritt, J. A., Brenner, C. A., Malter, H. E. & Cohen, J. Mitochondria in human offspring derived from ooplasmic transplantation. Hum. Reprod. 16, 513–516 (2001).

    CAS  PubMed  Google Scholar 

  103. Krammer, P. H. CD95's deadly mission in the immune system. Nature 407, 789–795 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is indebted to the many past and current members of his laboratory, as well as to a number of colleagues and collaborators for their invaluable contributions, who collectively have made this review possible. The author also gratefully acknowledges the U.S. National Institutes of Health, the Department of Defense–U.S. Army Medical Research and Materiel Command's Office of Congressionally Directed Medical Research, the Steven and Michele Kirsch Foundation, and the Vincent Memorial Hospital Board of Trustees for their generous support of this work. The author apologizes for not citing other important contributions to the fields of programmed cell death and reproductive biology owing to space limitations.

Author information

Authors and Affiliations

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

    Jonathan L. Tilly

Authors
  1. Jonathan L. Tilly
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

FlyBase:

rpr

Dcp-1

grim

 LocusLink:

Aif

Atm

Bak

Bax

Bcl-2

Bcl-B

Bcl-rambo

Bcl-xL

Bid

Bim

Bok

endoG

Nix

PUMA

 Swiss-Prot:

acid sphingomyelinase

Ahr

Apaf-1

Bad

Bcl-GS

Bcl-w

Bfl1

Bik/Nbk

Blk

Bnip3

caspase-2

caspase-3

caspase-6

caspase-7

caspase-8

caspase-9

Hrk

SCF

Smac/DIABLO

 WormBase:

CED-3

CED-4

EGL-1

Glossary

OOGENESIS

The process of gamete formation in the female, which in mammals leads to the production of germ cells that are arrested in prophase-I of meiosis (oocytes) from a pool of mitotically active germ cells (oogonia).

DIAKINESIS

The point of the first meiotic block after the diploid germ cell in females (oogonium) progresses through the leptotene, zygotene and pachytene stages of prophase-I to become arrested in diplotene. In mammals, an oocyte reinitiates and completes meiosis-I after the preovulatory follicle that houses the oocyte receives the stimulus for ovulation.

PRIMORDIAL FOLLICLES

In vertebrates, each oocyte becomes enclosed by supportive somatic cells to form the most basic functional unit of the ovary, a follicle. The least differentiated type of follicle is referred to as primordial, being characterized by the presence of a single layer of squamous pre-granulosa somatic cells and its existence in a 'resting' state.

MENOPAUSE

A clinical diagnosis that is based on the permanent cessation of menses. In human females, the peri-menopausal period is usually heralded by infertility, near exhaustion of the oocyte reserve, a cessation of ovarian function and a loss of menstrual cyclicity. Only humans and nonhuman primates have menses, so other animal species cannot have a 'true' menopause.

HORMONE REPLACEMENT THERAPY

(HRT). A therapeutic preparation of oestrogens, usually combined with a small amount of progestins, that is prescribed to alleviate some of the physical and psychological manifestations of menopause which are believed to result from the loss of ovarian function.

ASSISTED REPRODUCTIVE TECHNOLOGIES

(ART). These are clinical procedures that are designed to help achieve pregnancy. Most of these procedures include the retrieval and fertilization of a woman's eggs outside the body (in vitro fertilization or IVF) followed by return of the embryos to the uterus (embryo transfer or ET) for implantation.

HISTOMORPHOMETRY

A process by which an ovary is removed, fixed, embedded in paraffin and serially sectioned. The sections are mounted in order on glass microscope slides and stained with a vital dye, such as haematoxylin–eosin. The total number of healthy versus dead/dying oocytes per section is then determined by light microscopic analysis.

PER–ARNT–SIM (PAS) FAMILY

A group of interacting and structurally related basic helix–loop–helix (bHLH) transcription factors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tilly, J. Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol 2, 838–848 (2001). https://doi.org/10.1038/35099086

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35099086

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