Abstract

Large-scale phenotyping efforts have demonstrated that approximately 25–30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies. Early lethality (embryonic days 9.5–14.5) is almost always associated with severe placental malformations. Placental defects correlate strongly with abnormal brain, heart and vascular development. Analysis of mutant trophoblast stem cells and conditional knockouts suggests that a considerable number of factors that cause embryonic lethality when ablated have primary gene function in trophoblast cells. Our data highlight the hugely under-appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes that govern placenta formation.

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Acknowledgements

We would like to thank N. Karp for expert advice on statistical analyses, I. Sealy for help with PCA analyses, the Flow Cytometry Facility at the Babraham Institute, as well as all contributors to the DMDD programme. This work was supported by Wellcome Trust Strategic Award WT100160MA.

Author information

Author notes

    • Vicente Perez-Garcia
    •  & Elena Fineberg

    These authors contributed equally to this work.

Affiliations

  1. The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK

    • Vicente Perez-Garcia
    • , Elena Fineberg
    • , Alexander Murray
    • , Arnold Sienerth
    •  & Myriam Hemberger
  2. Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

    • Vicente Perez-Garcia
    • , Elena Fineberg
    • , Alexander Murray
    • , Arnold Sienerth
    •  & Myriam Hemberger
  3. The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

    • Robert Wilson
    • , James C. Smith
    •  & Timothy Mohun
  4. Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK

    • Cecilia Icoresi Mazzeo
    • , Catherine Tudor
    • , Jacqueline K. White
    • , Elizabeth Tuck
    • , Edward J. Ryder
    • , Diane Gleeson
    • , Emma Siragher
    • , Hannah Wardle-Jones
    • , Nicole Staudt
    • , Neha Wali
    • , John Collins
    • , Elisabeth M. Busch-Nentwich
    • , Antonella Galli
    •  & David J. Adams
  5. Division of Anatomy, Center for Anatomy & Cell Biology, Medical University of Vienna, Waehringerstrasse 13, A-1090 Vienna, Austria

    • Stefan Geyer
    •  & Wolfgang J. Weninger
  6. Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK

    • Elisabeth M. Busch-Nentwich
  7. Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK

    • Elizabeth Robertson

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Contributions

V.P.-G., E.F., A.M., A.S. and M.H. performed the core experiments including histological analyses and TSC work; R.W. performed statistical co-association analyses and DMDD webpage data handling; C.I.M., C.T., J.K.W., E.T., E.J.R., D.G., E.S., H.W.-J. and A.G. performed all mouse colony management, breeding, sample collection and genotyping work; N.S., N.W., J.C. and E.M.B.-N. performed transcriptomics analyses; S.G., W.J.W. and T.M. performed HREM imaging and analyses, J.C.S, E.J.R., D.J.A., T.M. and M.H. designed the study, interpreted results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Myriam Hemberger.

Reviewer Information Nature thanks J. Cross, E. Lacy and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Table 4

    This table contains a list of primers and gRNAs.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains a summary of all mutant mouse lines analysed.

  2. 2.

    Supplementary Table 2

    This table contains phenotyping terms that are significantly enriched in mutant lines with placental defect.

  3. 3.

    Supplementary Table 3

    This table contains mouse phenotyping (MP) terms used for penetrance analysis.

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DOI

https://doi.org/10.1038/nature26002

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