Letter | Published:

Principles of early human development and germ cell program from conserved model systems

Nature volume 546, pages 416420 (15 June 2017) | Download Citation

Abstract

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate during weeks 2–3 of early post-implantation development1. Using in vitro models of hPGC induction2,3,4, recent studies have suggested that there are marked mechanistic differences in the specification of human and mouse PGCs5. This may be due in part to the divergence in their pluripotency networks and early post-implantation development6,7,8. As early human embryos are not accessible for direct study, we considered alternatives including porcine embryos that, as in humans, develop as bilaminar embryonic discs. Here we show that porcine PGCs originate from the posterior pre-primitive-streak competent epiblast by sequential upregulation of SOX17 and BLIMP1 in response to WNT and BMP signalling. We use this model together with human and monkey in vitro models simulating peri-gastrulation development to show the conserved principles of epiblast development for competency for primordial germ cell fate. This process is followed by initiation of the epigenetic program9,10,11 and regulated by a balanced SOX17BLIMP1 gene dosage. Our combinatorial approach using human, porcine and monkey in vivo and in vitro models provides synthetic insights into early human development.

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Acknowledgements

We thank R. Campbell and C. Lee for help with animals and hPSCs, A. Riddell for FACS and T. Otani for advice on cmPSCs. T.K. was supported by JSPS, the Uehara and Kanae Foundations; H.Z. by CSC; D.A.C. by CONACYT. The work was funded by BBSRC grant to R.A., C.A. and M.A.S (BB/M001466/1). M.A.S is a Wellcome Investigator.

Author information

Author notes

    • David A. Contreras

    Present address: CEIEPAA-FMVZ-UNAM, Tequisquiapan, Queretaro 76790, Mexico.

    • Toshihiro Kobayashi
    •  & Haixin Zhang

    These authors contributed equally to this work.

Affiliations

  1. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK

    • Toshihiro Kobayashi
    • , Walfred W. C. Tang
    • , Naoko Irie
    • , Anastasiya Sybirna
    • , Sabine Dietmann
    •  & M. Azim Surani
  2. Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK

    • Toshihiro Kobayashi
    • , Walfred W. C. Tang
    • , Naoko Irie
    • , Anastasiya Sybirna
    •  & M. Azim Surani
  3. School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK

    • Haixin Zhang
    • , Sarah Withey
    • , Doris Klisch
    • , David A. Contreras
    • , Robert Webb
    •  & Ramiro Alberio
  4. Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK

    • Anastasiya Sybirna
    •  & Sabine Dietmann
  5. School of Veterinary Medicine and Sciences, University of Nottingham, Loughborough LE12 5RD, UK

    • Cinzia Allegrucci

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Contributions

T.K. designed the experiments and performed cell culture, plasmid construction, immunofluorescence, qPCR, RNA-seq, western blots, data analysis and wrote the paper. W.W.C.T. designed experiments and analysed RNA-seq. N.I. performed preliminary work and designed experiments, and S.D. performed bioinformatics. A.S. helped with a hPSC reporter. H.Z., S.W., D.K. and C.A. designed and performed immunofluorescence and culture of pig embryos and epiblasts. D.A.C. and R.W. designed and performed in situ hybridization experiments and immunofluorescence. W.W.C.T., N.I. and S.W. made equal contributions. R.A. supervised the project, designed experiments, performed dissections and wrote the paper. M.A.S. supervised the project, designed experiments, and wrote the paper. All authors contributed to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ramiro Alberio or M. Azim Surani.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains the uncropped gels and Supplementary Tables 2-3.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains a list of hPGC specific genes used for GSEA analysis.

About this article

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DOI

https://doi.org/10.1038/nature22812

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