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.

  • Letter
  • Published:

Prometaphase APCcdh1 activity prevents non-disjunction in mammalian oocytes

Nature Cell Biology volume 9, pages 1192–1198 (2007)Cite this article

Abstract

The first female meiotic division (meiosis I, MI) is uniquely prone to chromosome segregation errors through non-disjunction, resulting in trisomies and early pregnancy loss1. Here, we show a fundamental difference in the control of mammalian meiosis that may underlie such susceptibility. It involves a reversal in the well-established timing of activation of the anaphase-promoting complex (APC)2,3 by its co-activators cdc20 and cdh1. APCcdh1 was active first, during prometaphase I, and was needed in order to allow homologue congression, as loss of cdh1 speeded up MI, leading to premature chromosome segregation and a non-disjunction phenotype. APCcdh1 targeted cdc20 for degradation, but did not target securin or cyclin B1. These were degraded later in MI through APCcdc20, making cdc20 re-synthesis essential for successful meiotic progression. The switch from APCcdh1 to APCcdc20 activity was controlled by increasing CDK1 and cdh1 loss. These findings demonstrate a fundamentally different mechanism of control for the first meiotic division in mammalian oocytes that is not observed in meioses of other species.

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: Cdh1 loss accelerated meiosis I, leading to premature homologue segregation and non-disjunction.
Figure 2: Premature cyclin B1 degradation following cdh1 knockdown.
Figure 3: Cdc20 degradation precedes that of cyclin B1 and securin during meiosis I.
Figure 4: Essential role of cdc20 in meiosis I.
Figure 5: CDK1 regulation of prometaphase APCcdh1.

Similar content being viewed by others

References

  1. Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev. Genet. 2, 280–291 (2001).

    Article  CAS  Google Scholar 

  2. Acquaviva, C. & Pines, J. The anaphase-promoting complex/cyclosome: APC/C. J. Cell Sci. 119, 2401–2404 (2006).

    Article  CAS  Google Scholar 

  3. Peters, J. M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nature Rev. Mol. Cell Biol. 7, 644–656 (2006).

    Article  CAS  Google Scholar 

  4. Bashir, T., Dorrello, N. V., Amador, V., Guardavaccaro, D. & Pagano, M. Control of the SCFSkp2-Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligase. Nature 428, 190–193 (2004).

    Article  CAS  Google Scholar 

  5. Wei, W. et al. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428, 194–198 (2004).

    Article  CAS  Google Scholar 

  6. Pines, J. Mitosis: a matter of getting rid of the right protein at the right time. Trends Cell Biol. 16, 55–63 (2006).

    Article  CAS  Google Scholar 

  7. Reis, A., Chang, H. Y., Levasseur, M. & Jones, K. T. APCcdh1 activity in mouse oocytes prevents entry into the first meiotic division. Nature Cell Biol. 8, 539–540 (2006).

    Article  CAS  Google Scholar 

  8. Marangos, P., Verschuren, E. W., Chen, R., Jackson, P. K. & Carroll, J. Prophase I arrest and progression to metaphase I in mouse oocytes are controlled by Emi1-dependent regulation of APCCdh1. J. Cell Biol. 176, 65–75 (2007).

    Article  CAS  Google Scholar 

  9. Homer, H. A. et al. Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes Dev. 19, 202–207 (2005).

    Article  CAS  Google Scholar 

  10. Hagting, A. et al. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J. Cell Biol. 157, 1125–1137 (2002).

    Article  CAS  Google Scholar 

  11. Herbert, M. et al. Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nature Cell Biol. 5, 1023–1025 (2003).

    Article  CAS  Google Scholar 

  12. Hampl, A. & Eppig, J. J. Analysis of the mechanism(s) of metaphase I arrest in maturing mouse oocytes. Development 121, 925–933 (1995).

    CAS  PubMed  Google Scholar 

  13. Vodermaier, H. C., Gieffers, C., Maurer-Stroh, S., Eisenhaber, F. & Peters, J. M. TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1. Curr. Biol. 13, 1459–1468 (2003).

    Article  CAS  Google Scholar 

  14. Rape, M., Reddy, S. K. & Kirschner, M. W. The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell 124, 89–103 (2006).

    Article  CAS  Google Scholar 

  15. Binne, U. K. et al. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nature Cell Biol. 9, 225–232 (2007).

    Article  CAS  Google Scholar 

  16. Wan, Y., Liu, X. & Kirschner, M. W. The anaphase-promoting complex mediates TGF-β signaling by targeting SnoN for destruction. Mol. Cell 8, 1027–1039 (2001).

    Article  CAS  Google Scholar 

  17. Jeganathan, K. B., Malureanu, L. & van Deursen, J. M. The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 438, 1036–1039 (2005).

    Article  CAS  Google Scholar 

  18. Salah, S. M. & Nasmyth, K. Destruction of the securin Pds1p occurs at the onset of anaphase during both meiotic divisions in yeast. Chromosoma 109, 27–34 (2000).

    Article  CAS  Google Scholar 

  19. Taieb, F. E., Gross, S. D., Lewellyn, A. L. & Maller, J. L. Activation of the anaphase-promoting complex and degradation of cyclin B is not required for progression from Meiosis I to II in Xenopus oocytes. Curr. Biol. 11, 508–513 (2001).

    Article  CAS  Google Scholar 

  20. Peter, M. et al. The APC is dispensable for first meiotic anaphase in Xenopus oocytes. Nature Cell Biol. 3, 83–87 (2001).

    Article  CAS  Google Scholar 

  21. Lee, B. H. & Amon, A. Role of Polo-like kinase CDC5 in programming meiosis I chromosome segregation. Science 300, 482–486 (2003).

    Article  CAS  Google Scholar 

  22. Kitagawa, R., Law, E., Tang, L. & Rose, A. M. The Cdc20 homolog, FZY-1, and its interacting protein, IFY-1, are required for proper chromosome segregation in Caenorhabditis elegans. Curr. Biol. 12, 2118–2123 (2002).

    Article  CAS  Google Scholar 

  23. Zachariae, W., Schwab, M., Nasmyth, K. & Seufert, W. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282, 1721–1724 (1998).

    Article  CAS  Google Scholar 

  24. Listovsky, T., Zor, A., Laronne, A. & Brandeis, M. Cdk1 is essential for mammalian cyclosome/APC regulation. Exp. Cell Res. 255, 184–191 (2000).

    Article  CAS  Google Scholar 

  25. Listovsky, T. et al. Mammalian Cdh1/Fzr mediates its own degradation. EMBO J. 23, 1619–1626 (2004).

    Article  CAS  Google Scholar 

  26. Benmaamar, R. & Pagano, M. Involvement of the SCF complex in the control of Cdh1 degradation in S-phase. Cell Cycle 4, 1230–1232 (2005).

    Article  CAS  Google Scholar 

  27. Brunet, S., Pahlavan, G., Taylor, S. & Maro, B. Functionality of the spindle checkpoint during the first meiotic division of mammalian oocytes. Reproduction 126, 443–450 (2003).

    Article  CAS  Google Scholar 

  28. Wassmann, K., Niault, T. & Maro, B. Metaphase I arrest upon activation of the Mad2-dependent spindle checkpoint in mouse oocytes. Curr. Biol. 13, 1596–1608 (2003).

    Article  CAS  Google Scholar 

  29. LeMaire-Adkins, R., Radke, K. & Hunt, P. A. Lack of checkpoint control at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in mammalian females. J. Cell Biol. 139, 1611–1619 (1997).

    Article  CAS  Google Scholar 

  30. Gorr, I. H. et al. Essential CDK1-inhibitory role for separase during meiosis I in vertebrate oocytes. Nature Cell Biol. 8, 1035–1037 (2006).

    Article  CAS  Google Scholar 

  31. Madgwick, S., Hansen, D. V., Levasseur, M., Jackson, P. K. & Jones, K. T. Mouse Emi2 is required to enter meiosis II by reestablishing cyclin B1 during interkinesis. J. Cell Biol. 174, 791–801 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the technical support of Olaf Stemmann (Max Planck Institute of Biochemistry, Munich, Germany) in performing the H1 kinase assays. This work was supported by a grant from the Wellcome Trust to K.T.J.

Author information

Authors and Affiliations

  1. Institute for Cell and Molecular Biosciences, The Medical School, Framlington Place, University of Newcastle, Newcastle, NE2 4HH, UK

    Alexandra Reis, Suzanne Madgwick, Heng-Yu Chang, Ibtissem Nabti, Mark Levasseur & Keith T. Jones

Authors
  1. Alexandra Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suzanne Madgwick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heng-Yu Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ibtissem Nabti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark Levasseur
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keith T. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.T.J. directed the work. A.R. and S.M. performed most of the experiments, with H.-Y.C making the initial observations on the effects of the cdh1MO, I.N. performing some of the western blots and M.L. making some of the constructs. K.T.J. wrote the paper in consultation with A.R. and S.M.

Corresponding author

Correspondence to Keith T. Jones.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3 and S4 (PDF 240 kb)

Supplementary Information

Supplementary Movie 1 (AVI 2851 kb)

Supplementary Information

Supplementary Movie 2 (AVI 2456 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reis, A., Madgwick, S., Chang, HY. et al. Prometaphase APCcdh1 activity prevents non-disjunction in mammalian oocytes. Nat Cell Biol 9, 1192–1198 (2007). https://doi.org/10.1038/ncb1640

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1640

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