Article | Published:

Zinc availability regulates exit from meiosis in maturing mammalian oocytes

Nature Chemical Biology volume 6, pages 674681 (2010) | Download Citation

Abstract

Cellular metal ion fluxes are known in alkali and alkaline earth metals but are not well documented in transition metals. Here we describe major changes in the zinc physiology of the mammalian oocyte as it matures and initiates embryonic development. Single-cell elemental analysis of mouse oocytes by synchrotron-based X-ray fluorescence microscopy (XFM) revealed a 50% increase in total zinc content within the 12–14-h period of meiotic maturation. Perturbation of zinc homeostasis with a cell-permeable small-molecule chelator blocked meiotic progression past telophase I. Zinc supplementation rescued this phenotype when administered before this meiotic block. However, after telophase arrest, zinc triggered parthenogenesis, suggesting that exit from this meiotic step is tightly regulated by the availability of a zinc-dependent signal. These results implicate the zinc bolus acquired during meiotic maturation as an important part of the maternal legacy to the embryo.

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References

  1. 1.

    & Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 14, 331–341 (2001).

  2. 2.

    & New roles for copper metabolism in cell proliferation, signaling, and disease. J. Biol. Chem. 284, 717–721 (2009).

  3. 3.

    & Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J. Biol. Chem. 284, 711–715 (2009).

  4. 4.

    et al. Zinc is a novel intracellular second messenger. J. Cell Biol. 177, 637–645 (2007).

  5. 5.

    , & Redox signaling and cancer: the role of “labile” iron. Cancer Lett. 266, 21–29 (2008).

  6. 6.

    Zinc transporters and the cellular trafficking of zinc. Biochim. Biophys. Acta 1763, 711–722 (2006).

  7. 7.

    , & The genetics of essential metal homeostasis during development. Genesis 46, 214–228 (2008).

  8. 8.

    Transition metals in control of gene expression. Science 261, 715–725 (1993).

  9. 9.

    , & Metals, toxicity and oxidative stress. Curr. Med. Chem. 12, 1161–1208 (2005).

  10. 10.

    & Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292, 2488–2492 (2001).

  11. 11.

    & Transition metal speciation in the cell: insights from the chemistry of metal ion receptors. Science 300, 931–936 (2003).

  12. 12.

    , , & Zinc ions and cation diffusion facilitator proteins regulate Ras-mediated signaling. Dev. Cell 2, 567–578 (2002).

  13. 13.

    , & Zinc, iron, and copper contents of Xenopus laevis oocytes and embryos. Mol. Reprod. Dev. 36, 419–423 (1993).

  14. 14.

    , , , & Zinc regulates the ability of Cdc25C to activate MPF/cdk1. J. Cell. Physiol. 213, 98–104 (2007).

  15. 15.

    & Zinc physiology and biochemistry in oocytes and embryos. Biometals 14, 385–395 (2001).

  16. 16.

    , & Zinc uptake and distribution in Xenopus laevis oocytes and embryos. Biochemistry 34, 16524–16531 (1995).

  17. 17.

    & Regulation of the oocyte-to-zygote transition. Science 316, 407–408 (2007).

  18. 18.

    Oogenesis as a foundation for embryogenesis. Mol. Cell. Endocrinol. 186, 149–153 (2002).

  19. 19.

    & The maternal legacy to the embryo: cytoplasmic components and their effects on early development. Theriogenology 55, 1255–1276 (2001).

  20. 20.

    & Preservation of fertility in patients with cancer. N. Engl. J. Med. 360, 902–911 (2009).

  21. 21.

    , & The molecular basis of oocyte growth and development. Mol. Cell. Endocrinol. 145, 27–37 (1998).

  22. 22.

    , & Importance of glutathione in the acquisition and maintenance of sperm nuclear decondensing activity in maturing hamster oocytes. Dev. Biol. 125, 181–186 (1988).

  23. 23.

    , & Cytoplasmic maturation of mammalian oocytes: development of a mechanism responsible for sperm-induced Ca2+ oscillations. Reprod. Biol. 8, 3–22 (2008).

  24. 24.

    Oogenesis: variations on a theme. Dev. Genet. 16, 1–5 (1995).

  25. 25.

    & NIST critical stability constants of metal complexes. in NIST Standard Reference Database 46, v5.0 (Plenum, New York, 1998).

  26. 26.

    , , & Metallothionein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation. J. Biol. Chem. 274, 9183–9192 (1999).

  27. 27.

    , , , & Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas. A new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J. Biol. Chem. 260, 2719–2727 (1985).

  28. 28.

    & Allocation of gamma-tubulin between oocyte cortex and meiotic spindle influences asymmetric cytokinesis in the mouse oocyte. Biol. Reprod. 76, 949–957 (2007).

  29. 29.

    & Cytoskeleton and cell cycle control during meiotic maturation of the mouse oocyte: integrating time and space. Reproduction 130, 801–811 (2005).

  30. 30.

    & Using immunofluorescence to observe methylation changes in mammalian preimplantation embryos. Methods Mol. Biol. 325, 129–137 (2006).

  31. 31.

    , , & Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol. 241, 172–182 (2002).

  32. 32.

    Comparative biology of calcium signaling during fertilization and egg activation in animals. Dev. Biol. 211, 157–176 (1999).

  33. 33.

    et al. Egg-to-embryo transition is driven by differential responses to Ca2+ oscillation number. Dev. Biol. 250, 280–291 (2002).

  34. 34.

    , , & Egg activation is the result of calcium signal summation in the mouse. Reproduction 131, 27–34 (2006).

  35. 35.

    , , & (eds.). Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 2003).

  36. 36.

    , & Emission ratiometric imaging of intracellular zinc: design of a benzoxazole fluorescent sensor and its application in two-photon microscopy. J. Am. Chem. Soc. 126, 712–713 (2004).

  37. 37.

    , & Meiotic competence acquisition is associated with the appearance of M-phase characteristics in growing mouse oocytes. Dev. Biol. 143, 162–172 (1991).

  38. 38.

    & Relationship between growth and meiotic maturation of the mouse oocyte. Dev. Biol. 50, 531–536 (1976).

  39. 39.

    & In vitro maturation of mouse oocytes isolated from late, middle, and pre-antral graafian follicles. J. Exp. Zool. 190, 123–127 (1974).

  40. 40.

    et al. Meiotic abnormalities of c-mos knockout mouse oocytes: activation after first meiosis or entrance into third meiotic metaphase. Biol. Reprod. 55, 1315–1324 (1996).

  41. 41.

    , , & Relationship between the developmental programs controlling nuclear and cytoplasmic maturation of mouse oocytes. Dev. Biol. 164, 1–9 (1994).

  42. 42.

    , , , & Ca2+ oscillatory pattern in fertilized mouse eggs affects gene expression and development to term. Dev. Biol. 300, 534–544 (2006).

  43. 43.

    MAPS: A set of software tools for analysis and visualization of 3D X-ray fluorescence data sets. J. Phys. IV France 104, 635–638 (2003).

  44. 44.

    , , , & Genetic strain variations in the metaphase-II phenotype of mouse oocytes matured in vivo or in vitro. Reproduction 130, 845–855 (2005).

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Acknowledgements

The authors gratefully acknowledge J. Jozefik, S. Kiesewetter and D. Mackovic for animal care and concerns. We would also like to thank the P01 Histology Core (T. Wellington, director), the Analytical Services Laboratory and the Quantitative Bioelement Imaging Center in the Chemistry of Life Processes Institute at Northwestern University for reagents and discussions regarding sample processing. This work is supported by US National Institutes of Health grants P01 HD021921 and GM38784, the W.M. Keck Foundation Medical Research Award and the Chicago Biomedical Consortium Spark Award. A.M.K. was a fellow of the Reproductive Biology Training Grant HD007068. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the Office of Basic Energy Sciences in the Office of Science of the US Department of Energy, under contract no. DE-AC02-06CH11357.

Author information

Affiliations

  1. Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

    • Alison M Kim
    •  & Teresa K Woodruff
  2. The Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, USA.

    • Alison M Kim
    •  & Thomas V O'Halloran
  3. X-ray Science Division, Argonne National Laboratory, Argonne, Illinois, USA.

    • Stefan Vogt
  4. Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois, USA.

    • Thomas V O'Halloran
    •  & Teresa K Woodruff
  5. Department of Chemistry, Northwestern University, Evanston, Illinois, USA.

    • Thomas V O'Halloran

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Contributions

A.M.K., T.V.O. and T.K.W. designed the research and wrote the manuscript. A.M.K. performed the research. S.V. provided XFM data analysis and technical support.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Thomas V O'Halloran or Teresa K Woodruff.

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DOI

https://doi.org/10.1038/nchembio.419

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