Skip to main content

Thank you for visiting 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:

The first cleavage of the mouse zygote predicts the blastocyst axis


One of the unanswered questions in mammalian development is how the embryonic–abembryonic axis of the blastocyst is first established. It is possible that the first cleavage division contributes to this process, because in most mouse embryos the progeny of one two-cell blastomere primarily populate the embryonic part of the blastocyst and the progeny of its sister populate the abembryonic part1,2,3,4. However, it is not known whether the embryonic–abembryonic axis is set up by the first cleavage itself, by polarity in the oocyte that then sets the first cleavage plane with respect to the animal pole, or indeed whether it can be divorced entirely from the first cleavage and established in relation to the animal pole. Here we test the importance of the orientation of the first cleavage by imposing an elongated shape on the zygote so that the division no longer passes close to the animal pole, marked by the second polar body. Non-invasive lineage tracing shows that even when the first cleavage occurs along the short axis imposed by this experimental treatment, the progeny of the resulting two-cell blastomeres tend to populate the respective embryonic and abembryonic parts of the blastocyst. Thus, the first cleavage contributes to breaking the symmetry of the embryo, generating blastomeres with different developmental characteristics.

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

Access options

Buy this article

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

Figure 1: Orientation of the first cleavage division.
Figure 2: Cytochalasin treatment before pronuclei migration changes the orientation of the first cleavage division.
Figure 3: Relationship between final position of pronuclei, long axis of zygote and first cleavage in experimentally elongated zygotes.
Figure 4: Outcome of changing orientation of first cleavage on the orientation of blastocyst embryonic–abembryonic axis.

Similar content being viewed by others


  1. Piotrowska, K. & Zernicka-Goetz, M. Role for sperm in spatial patterning of early mouse embryos. Nature 409, 517–521 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Gardner, R. L. Specification of embryonic axes begins before cleavage in normal mouse development. Development 128, 839–847 (2001)

    CAS  PubMed  Google Scholar 

  3. Piotrowska, K., Wianny, F., Pedersen, R. A. & Zernicka-Goetz, M. Blastomeres arising from the first cleavage division have distinguishable fates in normal mouse development. Development 128, 3739–3748 (2001)

    CAS  PubMed  Google Scholar 

  4. Fujimori, T., Kurotaki, Y., Miyazaki, J. I. & Nabeshima, Y. I. Analysis of cell lineage in 2- and 4-cell mouse embryos. Development 21, 5113–5122 (2003)

    Article  Google Scholar 

  5. Piotrowska-Nitsche, K. & Zernicka-Goetz, M. Spatial arrangement of individual 4-cell stage blastomeres and the order in which they are generated correlate with blastocyst pattern in the mouse embryo. Mech. Dev. advance online publication, 18 December 2004 (doi:10.1016/j.mod.2004.11.014).

  6. Piotrowska-Nitsche, K., Perea-Gomez, A., Haraguchi, S. & Zernicka-Goetz, M. Four-cell stage mouse blastomeres have different developmental properties. Development 132, 479–490 (2005)

    Article  CAS  Google Scholar 

  7. Gardner, R. L. The early blastocyst is bilaterally symmetrical and its axis of symmetry is aligned with the animal–vegetal axis of the zygote in the mouse. Development 124, 289–301 (1997)

    CAS  PubMed  Google Scholar 

  8. Plusa, B., Grabarek, J. B., Piotrowska, K., Glover, D. M. & Zernicka-Goetz, M. Site of the previous meiotic division defines cleavage orientation in the mouse embryo. Nature Cell Biol. 4, 811–815 (2002)

    Article  CAS  Google Scholar 

  9. Gray, D. et al. First cleavage of the mouse embryos responds to change in egg shape at fertilisation. Curr. Biol. 14, 397–405 (2004)

    Article  CAS  Google Scholar 

  10. Hadjantonakis, A.-K. & Papaioannou, V. High resolution dynamic in vivo imaging and tracking in mice. BMC Biotechnol. 4, 33 (2004)

    Article  Google Scholar 

  11. Mayer, W., Smith, A., Fundele, R. & Haaf, T. Spatial separation of parental genomes in preimplantation mouse embryos. J. Cell Biol. 148, 629–634 (2000)

    Article  CAS  Google Scholar 

  12. Donahue, R. P. Fertilization of the mouse oocyte: sequence and timing of nuclear progression to the two-cell stage. J. Exp. Zool. 180, 305–318 (1972)

    Article  CAS  Google Scholar 

  13. Hiiragi, T. & Solter, D. First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing pronuclei. Nature 430, 360–364 (2004)

    Article  ADS  CAS  Google Scholar 

  14. Garner, W. & McLaren, A. Cell distribution in chimaeric mouse embryos before implantation. J. Embryol. Exp. Morphol. 32, 495–503 (1974)

    CAS  PubMed  Google Scholar 

Download references


This work was supported by a Wellcome Trust Senior Research Fellowship to M.Z.-G. and a BBSRC Project Grant to M.Z.-G. and D.M.G. K.P.N. was holding a Marie Curie Fellowship from the European Union. V.E.P. acknowledges support from the NIH. B.P. is on leave from the Department of Experimental Embryology at The Polish Academy of Science, Jastrzebic, Poland.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Magdalena Zernicka-Goetz.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Movie S1

Time-lapse image of first cleavage in zygotes expressing H2B-EGFP. The first cleavage in a series of 7 zygotes that divided during time-lapse imaging of 14 embryos. The PB lies within 30° of the plane defined by the metaphase plate position in 6 zygotes. (MOV 3009 kb)

Supplementary Movie S2

Time-lapse DIC/ fluorescence images of zygotes expressing H2B-EGFP and with marked sperm entry site. The sperm entry site was marked with a fluorescent bead as previously described3. (MOV 1250 kb)

Supplementary Movie S3

Time-lapse images of first cleavage division in zygotes in which the animal pole was transplanted to 90° of its original position. The first cleavage in this series of 7 embryos lies within 30° of the new position of the PB in 6 cases. The protocol for transplantation is as previously described8. (MOV 3734 kb)

Supplementary Movie S4 section 2

Time-lapse images of a series of control embryos tracking the path of pronuclei migration. Movie in 5 sections. (MOV 4501 kb)

Supplementary Movie S4 section 3 (MOV 3934 kb)

Supplementary Movie S4 section 4 (MOV 4122 kb)

Supplementary Movie S4 section 5 (MOV 4872 kb)

Supplementary Movie S4 section 6 (MOV 4829 kb)

Supplementary Movie S5 section 2

Time-lapse images of a series of embryos treated for 4 h with 5 g/ml cytochalasin B to depolymerise actin filaments during the time of pronuclei migration. Movie in 6 sections. (MOV 4298 kb)

Supplementary Movie S5 section 3 (MOV 4900 kb)

Supplementary Movie S5 section 4 (MOV 5015 kb)

Supplementary Movie S5 section 5 (MOV 4731 kb)

Supplementary Movie S5 section 6 (MOV 3996 kb)

Supplementary Movie S5 section 7 (MOV 5107 kb)

Supplementary Figure S1

Positions of clones derived from 2-cell blastomeres from experimentally elongated zygotes in relation to blastocyst morphology. (DOC 245 kb)

Supplementary Figure Legend

Legend to accompany the above Supplementary Figure. (DOC 21 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Plusa, B., Hadjantonakis, AK., Gray, D. et al. The first cleavage of the mouse zygote predicts the blastocyst axis. Nature 434, 391–395 (2005).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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