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.

  • Article
  • Published:

Oocyte differentiation is genetically dissociable from meiosis in mice

Nature Genetics volume 45, pages 877–883 (2013)Cite this article

Subjects

Abstract

Oogenesis is the process by which ovarian germ cells undertake meiosis and differentiate to become eggs. In mice, Stra8 is required for the chromosomal events of meiosis to occur, but its role in differentiation remains unknown. Here we report Stra8-deficient ovarian germ cells that grow and differentiate into oocyte-like cells that synthesize zonae pellucidae, organize surrounding somatic cells into follicles, are ovulated in response to hormonal stimulation, undergo asymmetric cell division to produce a polar body and cleave to form two-cell embryos upon fertilization. These events occur without premeiotic chromosomal replication, sister chromatid cohesion, synapsis or recombination. Thus, oocyte growth and differentiation are genetically dissociable from the chromosomal events of meiosis. These findings open to study the independent contributions of meiosis and oocyte differentiation to the making of a functional egg.

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: Stra8-deficient ovarian germ cells differentiate into oocyte-like cells.
Figure 2: A Stra8-deficient oocyte-like cell displays the ultrastructural features of a wild-type oocyte.
Figure 3: Stra8-deficient oocyte-like cells grow and differentiate without meiotic prophase.
Figure 4: Stra8-deficient oocyte-like cells organize ovulation-competent follicles.
Figure 5: Stra8-deficient oocyte-like cells divide asymmetrically upon maturation.
Figure 6: Premeiotic chromosome replication is dispensable for oocyte differentiation.
Figure 7: Stra8-deficient oocyte-like cells cleave to yield two-cell embryos upon fertilization.
Figure 8: A proposed model for the initiation of both meiosis (top) and oocyte growth and differentiation (bottom) in the mouse ovary.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. McLaren, A. Primordial germ cells in the mouse. Dev. Biol. 262, 1–15 (2003).

    CAS  PubMed  Google Scholar 

  2. Gill, M.E., Hu, Y.C., Lin, Y. & Page, D.C. Licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells. Proc. Natl. Acad. Sci. USA 108, 7443–7448 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lin, Y., Gill, M.E., Koubova, J. & Page, D.C. Germ cell–intrinsic and –extrinsic factors govern meiotic initiation in mouse embryos. Science 322, 1685–1687 (2008).

    CAS  PubMed  Google Scholar 

  4. McLaren, A. Meiosis and differentiation of mouse germ cells. Symp. Soc. Exp. Biol. 38, 7–23 (1984).

    CAS  PubMed  Google Scholar 

  5. McLaren, A. & Southee, D. Entry of mouse embryonic germ cells into meiosis. Dev. Biol. 187, 107–113 (1997).

    CAS  PubMed  Google Scholar 

  6. Adams, I.R. & McLaren, A. Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. Development 129, 1155–1164 (2002).

    CAS  PubMed  Google Scholar 

  7. Bowles, J. et al. Retinoid signaling determines germ cell fate in mice. Science 312, 596–600 (2006).

    CAS  PubMed  Google Scholar 

  8. Kocer, A., Reichmann, J., Best, D. & Adams, I.R. Germ cell sex determination in mammals. Mol. Hum. Reprod. 15, 205–213 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bowles, J. & Koopman, P. Sex determination in mammalian germ cells: extrinsic versus intrinsic factors. Reproduction 139, 943–958 (2010).

    CAS  PubMed  Google Scholar 

  10. Krentz, A.D. et al. DMRT1 promotes oogenesis by transcriptional activation of Stra8 in the mammalian fetal ovary. Dev. Biol. 356, 63–70 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Baltus, A.E. et al. In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nat. Genet. 38, 1430–1434 (2006).

    CAS  PubMed  Google Scholar 

  12. Anderson, E.L. et al. Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc. Natl. Acad. Sci. USA 105, 14976–14980 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Page, A.W. & Orr-Weaver, T.L. Stopping and starting the meiotic cell cycle. Curr. Opin. Genet. Dev. 7, 23–31 (1997).

    CAS  PubMed  Google Scholar 

  14. Von Stetina, J.R. & Orr-Weaver, T.L. Developmental control of oocyte maturation and egg activation in metazoan models. Cold Spring Harb. Perspect. Biol. 3, a005553 (2011).

    PubMed  PubMed Central  Google Scholar 

  15. Paredes, A. et al. Loss of synaptonemal complex protein-1, a synaptonemal complex protein, contributes to the initiation of follicular assembly in the developing rat ovary. Endocrinology 146, 5267–5277 (2005).

    CAS  PubMed  Google Scholar 

  16. Hübner, K. et al. Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256 (2003).

    PubMed  Google Scholar 

  17. Lacham-Kaplan, O., Chy, H. & Trounson, A. Testicular cell conditioned medium supports differentiation of embryonic stem cells into ovarian structures containing oocytes. Stem Cells 24, 266–273 (2006).

    PubMed  Google Scholar 

  18. Qing, T. et al. Induction of oocyte-like cells from mouse embryonic stem cells by co-culture with ovarian granulosa cells. Differentiation 75, 902–911 (2007).

    CAS  PubMed  Google Scholar 

  19. Kerkis, A. et al. In vitro differentiation of male mouse embryonic stem cells into both presumptive sperm cells and oocytes. Cloning Stem Cells 9, 535–548 (2007).

    CAS  PubMed  Google Scholar 

  20. Salvador, L.M., Silva, C.P., Kostetskii, I., Radice, G.L. & Strauss, J.F. III. The promoter of the oocyte-specific gene, Gdf9, is active in population of cultured mouse embryonic stem cells with an oocyte-like phenotype. Methods 45, 172–181 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nicholas, C.R., Haston, K.M., Grewall, A.K., Longacre, T.A. & Reijo Pera, R.A. Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility. Hum. Mol. Genet. 18, 4376–4389 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. White, Y.A. et al. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat. Med. 18, 413–421 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Novak, I. et al. Mouse embryonic stem cells form follicle-like ovarian structures but do not progress through meiosis. Stem Cells 24, 1931–1936 (2006).

    CAS  PubMed  Google Scholar 

  24. Oatley, J. & Hunt, P.A. Of mice and (wo)men: purified oogonial stem cells from mouse and human ovaries. Biol. Reprod. 86, 196 (2012).

    PubMed  PubMed Central  Google Scholar 

  25. Scherthan, H. Knockout mice provide novel insights into meiotic chromosome and telomere dynamics. Cytogenet. Genome Res. 103, 235–244 (2003).

    CAS  PubMed  Google Scholar 

  26. Rogakou, E.P., Pilch, D.R., Orr, A.H., Ivanova, V.S. & Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    CAS  PubMed  Google Scholar 

  27. Wassarman, P.M. & Josefowicz, W.J. Oocyte development in the mouse: an ultrastructural comparison of oocytes isolated at various stages of growth and meiotic competence. J. Morphol. 156, 209–235 (1978).

    CAS  PubMed  Google Scholar 

  28. Bishop, D.K., Park, D., Xu, L. & Kleckner, N. DMC1: a meiosis-specific yeast homolog of E. coli recA required for recombination, synaptonemal complex formation, and cell cycle progression. Cell 69, 439–456 (1992).

    CAS  PubMed  Google Scholar 

  29. Pittman, D.L. et al. Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol. Cell 1, 697–705 (1998).

    CAS  PubMed  Google Scholar 

  30. Yoshida, K. et al. The mouse RecA-like gene Dmc1 is required for homologous chromosome synapsis during meiosis. Mol. Cell 1, 707–718 (1998).

    CAS  PubMed  Google Scholar 

  31. Keeney, S., Giroux, C.N. & Kleckner, N. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88, 375–384 (1997).

    CAS  PubMed  Google Scholar 

  32. Baudat, F., Manova, K., Yuen, J.P., Jasin, M. & Keeney, S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol. Cell 6, 989–998 (2000).

    CAS  PubMed  Google Scholar 

  33. Di Giacomo, M. et al. Distinct DNA-damage–dependent and –independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc. Natl. Acad. Sci. USA 102, 737–742 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Su, Y.Q., Sugiura, K. & Eppig, J.J. Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin. Reprod. Med. 27, 32–42 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rajkovic, A., Pangas, S.A., Ballow, D., Suzumori, N. & Matzuk, M.M. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science 305, 1157–1159 (2004).

    CAS  PubMed  Google Scholar 

  36. Crisponi, L. et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat. Genet. 27, 159–166 (2001).

    CAS  PubMed  Google Scholar 

  37. Schmidt, D. et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131, 933–942 (2004).

    CAS  PubMed  Google Scholar 

  38. Eppig, J.J., Wigglesworth, K. & Chesnel, F. Secretion of cumulus expansion enabling factor by mouse oocytes: relationship to oocyte growth and competence to resume meiosis. Dev. Biol. 158, 400–409 (1993).

    CAS  PubMed  Google Scholar 

  39. Sorensen, R.A. & Wassarman, P.M. Relationship between growth and meiotic maturation of the mouse oocyte. Dev. Biol. 50, 531–536 (1976).

    CAS  PubMed  Google Scholar 

  40. Woods, L.M. et al. Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. J. Cell Biol. 145, 1395–1406 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kouznetsova, A., Lister, L., Nordenskjold, M., Herbert, M. & Hoog, C. Bi-orientation of achiasmatic chromosomes in meiosis I oocytes contributes to aneuploidy in mice. Nat. Genet. 39, 966–968 (2007).

    CAS  PubMed  Google Scholar 

  42. Donahue, R.P. Maturation of the mouse oocyte in vitro. I. Sequence and timing of nuclear progression. J. Exp. Zool. 169, 237–249 (1968).

    CAS  PubMed  Google Scholar 

  43. Romanienko, P.J. & Camerini-Otero, R.D. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol. Cell 6, 975–987 (2000).

    CAS  PubMed  Google Scholar 

  44. Xu, H., Beasley, M.D., Warren, W.D., van der Horst, G.T. & McKay, M.J. Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev. Cell 8, 949–961 (2005).

    CAS  PubMed  Google Scholar 

  45. Bannister, L.A., Reinholdt, L.G., Munroe, R.J. & Schimenti, J.C. Positional cloning and characterization of mouse mei8, a disrupted allelle of the meiotic cohesin Rec8. Genesis 40, 184–194 (2004).

    CAS  PubMed  Google Scholar 

  46. Bowles, J. et al. FGF9 suppresses meiosis and promotes male germ cell fate in mice. Dev. Cell 19, 440–449 (2010).

    CAS  PubMed  Google Scholar 

  47. Suzuki, A. & Saga, Y. Nanos2 suppresses meiosis and promotes male germ cell differentiation. Genes Dev. 22, 430–435 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Klar, A.J. Mating type functions for meiosis and sporulation in yeast act through cytoplasm. Genetics 94, 597–605 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ravi, M., Marimuthu, M.P. & Siddiqi, I. Gamete formation without meiosis in Arabidopsis. Nature 451, 1121–1124 (2008).

    CAS  PubMed  Google Scholar 

  50. Morgan, C.T., Noble, D. & Kimble, J. Mitosis-meiosis and sperm-oocyte fate decisions are separable regulatory events. Proc. Natl. Acad. Sci. USA 110, 3411–3416 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Schultz, R.M. The molecular foundations of the maternal to zygotic transition in the preimplantation embryo. Hum. Reprod. Update 8, 323–331 (2002).

    CAS  PubMed  Google Scholar 

  52. Wojtasz, L. et al. Meiotic DNA double-strand breaks and chromosome asynapsis in mice are monitored by distinct HORMAD2-independent and -dependent mechanisms. Genes Dev. 26, 958–973 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hayashi, K. et al. Offspring from oocytes derived from in vitro primordial germ cell–like cells in mice. Science 338, 971–975 (2012).

    CAS  PubMed  Google Scholar 

  54. Susiarjo, M., Rubio, C. & Hunt, P. Analyzing mammalian female meiosis. Methods Mol. Biol. 558, 339–354 (2009).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank C. Heyting (Agricultural University, Wageningen) for antiserum to REC8, N. Watson and L. Bechtold for assistance with electron microscopy and A. Amon, D. Bellott, M. Carmell, I. Cheeseman, D. de Rooij, R. Desgraz, T. Endo, G. Fink, M.A. Handel, T. Hassold, S. Hawley, A. Hochwagen, Y. Hu, J. Hughes, B. Lesch, J. Mueller, L. Okumura, T. Orr-Weaver, S. Repping, K. Romer and S. Soh for advice and comments on the manuscript. This work was supported by the Howard Hughes Medical Institute and the US National Institutes of Health (HD23839).

Author information

Authors and Affiliations

  1. Whitehead Institute, Cambridge, Massachusetts, USA

    Gregoriy A Dokshin, Andrew E Baltus & David C Page

  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Gregoriy A Dokshin, Andrew E Baltus & David C Page

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Gregoriy A Dokshin, Andrew E Baltus & David C Page

  4. The Jackson Laboratory, Bar Harbor, Maine, USA

    John J Eppig

Authors
  1. Gregoriy A Dokshin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew E Baltus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John J Eppig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David C Page
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.A.D., A.E.B., J.J.E. and D.C.P. designed the experiments. G.A.D. and J.J.E. performed the experiments. G.A.D. and D.C.P. wrote the manuscript.

Corresponding author

Correspondence to David C Page.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 5113 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dokshin, G., Baltus, A., Eppig, J. et al. Oocyte differentiation is genetically dissociable from meiosis in mice. Nat Genet 45, 877–883 (2013). https://doi.org/10.1038/ng.2672

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2672

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