Abstract

Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9-engineered live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WNT, however, endows cells with the competence to respond to graded levels of ACTIVIN, which induces differentiation without changing SMAD2 dynamics. This cellular memory of WNT signaling is necessary for ACTIVIN morphogen activity. A re-evaluation of the evidence gathered over decades in model systems, re-enforces our conclusions and points to an evolutionarily conserved mechanism.

Data availability

Sequencing data have been deposited in GEO under accession code GSE111717.

The following data sets were generated

Article and author information

Author details

  1. Anna Yoney

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4988-9237
  2. Fred Etoc

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Albert Ruzo

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Thomas Carroll

    Bioinformatics Resouce Center, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jakob J Metzger

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Iain Martyn

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Shu Li

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christoph Kirst

    Center for Studies in Physics and Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4867-5288
  9. Eric D Siggia

    Center for Studies in Physics and Biology, The Rockefeller University, New York, United States
    For correspondence
    siggiae@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7482-1854
  10. Ali H Brivanlou

    Laboratory of Stem Cell biology and Molecular Embryology, The Rockefeller University, New York, United States
    For correspondence
    brvnlou@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1761-280X

Funding

National Science Foundation (Graduate Research Fellowship DGE132526)

  • Anna Yoney

National Institute of General Medical Sciences (Research Project R01GM101653)

  • Eric D Siggia
  • Ali H Brivanlou

Eunice Kennedy Shriver National Institute of Child Health and Human Development (Research Project R01HD080699)

  • Eric D Siggia
  • Ali H Brivanlou

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lee L Rubin, Harvard Stem Cell Institute, Harvard University, United States

Version history

  1. Received: May 11, 2018
  2. Accepted: October 11, 2018
  3. Accepted Manuscript published: October 12, 2018 (version 1)
  4. Version of Record published: November 13, 2018 (version 2)

Copyright

© 2018, Yoney et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Anna Yoney
  2. Fred Etoc
  3. Albert Ruzo
  4. Thomas Carroll
  5. Jakob J Metzger
  6. Iain Martyn
  7. Shu Li
  8. Christoph Kirst
  9. Eric D Siggia
  10. Ali H Brivanlou
(2018)
WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids
eLife 7:e38279.
https://doi.org/10.7554/eLife.38279

Share this article

https://doi.org/10.7554/eLife.38279

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