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.

PRC1 coordinates timing of sexual differentiation of female primordial germ cells

Nature volume 495, pages 236–240 (2013)Cite this article

Subjects

Abstract

In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment1. In mouse female PGCs, expression of stimulated by retinoic acid gene 8 (Stra8) and meiosis are induced in response to retinoic acid provided from the mesonephroi2,3,4,5. Given the widespread role of retinoic acid signalling during development6,7, the molecular mechanisms that enable PGCs to express Stra8 and enter meiosis in a timely manner are unknown2,8. Here we identify gene-dosage-dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb repressive complex 1 (PRC1)9,10. Both paralogues are essential for PGC development between days 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs to maintain high levels of Oct4 (also known as Pou5f1) and Nanog expression11, and to prevent premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of retinoic acid signalling partially suppresses precocious Oct4 downregulation and Stra8 activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic retinoic acid signalling.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Rnf2 regulates PGC development and Oct4 and Nanog expression in Rnf2 cko female gonads.
Figure 2: Rnf2 deficiency induces extensive transcriptional misregulation in female PGCs.
Figure 3: Female Rnf2 Δ PGCs enter precociously into meiotic prophase.
Figure 4: PRC1 antagonizes retinoic acid signalling and maintains Stra8 in a repressive chromatin state.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray and RNA-sequencing data have been deposited in the Gene Expression Omnibus under accession numbers GSE42782 and GSE42852, respectively.

References

  1. Brennan, J. & Capel, B. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nature Rev. Genet. 5, 509–521 (2004)

    Article  CAS  Google Scholar 

  2. Menke, D. B., Koubova, J. & Page, D. C. Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. Dev. Biol. 262, 303–312 (2003)

    Article  CAS  Google Scholar 

  3. Koubova, J. et al. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc. Natl Acad. Sci. USA 103, 2474–2479 (2006)

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Deschamps, J. Ancestral and recently recruited global control of the Hox genes in development. Curr. Opin. Genet. Dev. 17, 422–427 (2007)

    Article  CAS  Google Scholar 

  7. Duester, G. Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921–931 (2008)

    Article  CAS  Google Scholar 

  8. Oulad-Abdelghani, M. et al. Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene. J. Cell Biol. 135, 469–477 (1996)

    Article  CAS  Google Scholar 

  9. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nature Rev. Cancer 6, 846–856 (2006)

    Article  CAS  Google Scholar 

  10. Posfai, E. et al. Polycomb function during oogenesis is required for mouse embryonic development. Genes Dev. 26, 920–932. (2012)

    Article  CAS  Google Scholar 

  11. Saitou, M., Kagiwada, S. & Kurimoto, K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139, 15–31 (2012)

    Article  CAS  Google Scholar 

  12. Simon, J. A. & Kingston, R. E. Mechanisms of polycomb gene silencing: knowns and unknowns. Nature Rev. Mol. Cell Biol. 10, 697–708 (2009)

    Article  CAS  Google Scholar 

  13. Di Carlo, A. & De Felici, M. A role for E-cadherin in mouse primordial germ cell development. Dev. Biol. 226, 209–219 (2000)

    Article  CAS  Google Scholar 

  14. Puschendorf, M. et al. PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nature Genet. 40, 411–420 (2008)

    Article  CAS  Google Scholar 

  15. Lomelí, H., Ramos-Mejia, V., Gertsenstein, M., Lobe, C. G. & Nagy, A. Targeted insertion of Cre recombinase into the TNAP gene: excision in primordial germ cells. Genesis 26, 116–117 (2000)

    Article  Google Scholar 

  16. Endoh, M. et al. Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development 135, 1513–1524 (2008)

    Article  CAS  Google Scholar 

  17. del Mar Lorente, M. et al. Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice. Development 127, 5093–5100 (2000)

    CAS  PubMed  Google Scholar 

  18. Yoshimizu, T. et al. Germline-specific expression of the Oct-4/green fluorescent protein (GFP) transgene in mice. Dev. Growth Differ. 41, 675–684 (1999)

    Article  CAS  Google Scholar 

  19. Leeb, M. et al. Polycomb complexes act redundantly to repress genomic repeats and genes. Genes Dev. 24, 265–276 (2010)

    Article  CAS  Google Scholar 

  20. 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)

    Article  CAS  Google Scholar 

  21. Yuan, L. et al. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296, 1115–1118 (2002)

    Article  CAS  ADS  Google Scholar 

  22. 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)

    Article  CAS  Google Scholar 

  23. Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nature Rev. Neurosci. 8, 755–765 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Hogarth, C. A. et al. Suppression of Stra8 expression in the mouse gonad by WIN 18,446. Biol. Reprod. 84, 957–965 (2011)

    Article  CAS  Google Scholar 

  26. Bel-Vialar, S. et al. Altered retinoic acid sensitivity and temporal expression of Hox genes in polycomb-M33-deficient mice. Dev. Biol. 224, 238–249 (2000)

    Article  CAS  Google Scholar 

  27. Dahl, J. A. & Collas, P. A rapid micro chromatin immunoprecipitation assay (ChIP). Nature Protocols 3, 1032–1045 (2008)

    Article  CAS  Google Scholar 

  28. Atsuta, T. et al. Production of monoclonal antibodies against mammalian Ring1B proteins. Hybridoma 20, 43–46 (2001)

    Article  CAS  Google Scholar 

  29. Zhou, Q. et al. Expression of stimulated by retinoic acid gene 8 (Stra8) and maturation of murine gonocytes and spermatogonia induced by retinoic acid in vitro. Biol. Reprod.. http://dx.doi.org/10.1095/biolreprod.107.064337 (2008)

  30. Lammers, J. H. et al. The gene encoding a major component of the lateral elements of synaptonemal complexes of the rat is related to X-linked lymphocyte-regulated genes. Mol. Cell. Biol. 14, 1137–1146 (1994)

    Article  CAS  Google Scholar 

  31. García, E., Marcos-Gutierrez, C., del Mar Lorente, M., Moreno, J. C. & Vidal, M. RYBP, a new repressor protein that interacts with components of the mammalian Polycomb complex, and with the transcription factor YY1. EMBO J. 18, 3404–3418 (1999)

    Article  Google Scholar 

  32. Peters, A. H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003)

    Article  CAS  Google Scholar 

  33. Tippmann, S. C. et al. Chromatin measurements reveal contributions of synthesis and decay to steady-state mRNA levels. Mol. Syst. Biol. 8, 593 (2012)

    Article  Google Scholar 

Download references

Acknowledgements

We thank A. Nagy and H. Schöler for the Tnap-cre and Oct4(ΔPE)–GFP mice, respectively, and M. Griswold for the Stra8 antibody. We are grateful to L. Gelman (microscopy and imaging), L. Burger, M. Stadler (bioinformatics), E. Cabuy, S. Thiry, K. Jacobeit (functional genomics) and the FMI animal facility for assistance. We thank members of the Peters laboratory, particularly M. Tardat, S. Erkek and M. Gill, for experimental support and discussions. S.Y. is a recipient of a Human Frontier Science Program long-term fellowship and a Japan Society for the Promotion of Science postdoctoral fellowship. Research in the Peters laboratory is supported by the Novartis Research Foundation, the Swiss National Science Foundation (31003A_125386 and NRP 63 - Stem Cells and Regenerative Medicine), SystemsX.ch (Cell plasticity), the Japanese Swiss Science and Technology Cooperation Program, the European Network of Excellence ‘The Epigenome’ and the EMBO Young Investigator program.

Author information

Author notes

  1. Shihori Yokobayashi

    Present address: Present address: Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan.,

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, CH-4058 Basel, Switzerland,

    Shihori Yokobayashi, Ching-Yeu Liang, Hubertus Kohler, Peter Nestorov, Zichuan Liu, Tim C. Roloff & Antoine H. F. M. Peters

  2. Faculty of Sciences, University of Basel, CH-4056 Basel, Switzerland,

    Ching-Yeu Liang, Peter Nestorov & Antoine H. F. M. Peters

  3. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain,

    Miguel Vidal

  4. Division of Molecular Genetics and Centre for Biomedical Genetics, the Netherlands Cancer Institute (NKI), 1066 CX Amsterdam, the Netherlands,

    Maarten van Lohuizen

Authors
  1. Shihori Yokobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ching-Yeu Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hubertus Kohler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Nestorov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zichuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miguel Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maarten van Lohuizen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tim C. Roloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antoine H. F. M. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.Y. and A.H.F.M.P. conceived and designed the experiments. S.Y. performed almost all experiments. C.-Y.L. performed μChIP experiments. H.K. performed FACS isolations. Z.L. isolated germinal vesicle oocytes. P.N. isolated RNA for RNA sequencing and provided advice on specific target amplification qRT-PCR. M.V. provided Ring1-deficient mice. M.v.L. provided Rnf2 conditionally deficient mice. T.C.R. assisted in microarray and RNA-sequencing analysis. S.Y., C.-Y.L. and A.H.F.M.P. analysed the data. S.Y. and A.H.F.M.P. wrote the manuscript.

Corresponding author

Correspondence to Antoine H. F. M. Peters.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11, full legends for Supplementary Tables 1 and 2 and Supplementary References. (PDF 5198 kb)

Supplementary Data

This file contains Supplementary Table 1, which shows lists of genes that are differentially expressed in Rnf2Δ and Ring1Δ/Rnf2Δ PGCs versus control PGCs as well as during development of normal PGCs according to microarray and RNA-sequencing analyses – see Supplementary Information pdf for full legend. (XLSX 362 kb)

Supplementary Data

This file contains Supplementary Table 2, which shows a list of GO terms that are over-represented in groups of genes mis-regulated in Rnf2Δ and Ring1Δ/Rnf2Δ PGCs. (XLSX 64 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yokobayashi, S., Liang, CY., Kohler, H. et al. PRC1 coordinates timing of sexual differentiation of female primordial germ cells. Nature 495, 236–240 (2013). https://doi.org/10.1038/nature11918

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11918

This article is cited by

Comments

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.

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