1. Developmental Biology
  2. Stem Cells and Regenerative Medicine
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Selective activation of FZD7 promotes mesendodermal differentiation of human pluripotent stem cells

  1. Diana Gumber
  2. Myan Do
  3. Neya Suresh Kumar
  4. Pooja R Sonavane
  5. Christina C N Wu
  6. Luisjesus S Cruz
  7. Stephanie Grainger
  8. Dennis Carson
  9. Terry Gaasterland
  10. Karl Willert  Is a corresponding author
  1. University of California, San Diego, United States
  2. San Diego State University, United States
Research Article
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Cite this article as: eLife 2020;9:e63060 doi: 10.7554/eLife.63060

Abstract

WNT proteins are secreted symmetry breaking signals that interact with cell surface receptors of the FZD family to regulate a multitude of developmental processes. Studying selectivity between WNTs and FZDs has been hampered by the paucity of purified WNT proteins and by their apparent non-selective interactions with the FZD receptors. Here we describe an engineered protein, called F7L6, comprised of antibody-derived single chain variable fragments, that selectively binds to human FZD7 and the co-receptor LRP6. F7L6 potently activates WNT/b-catenin signaling in a manner similar to Wnt3a. In contrast to Wnt3a, F7L6 engages only FZD7 and none of the other FZD proteins. Treatment of human pluripotent stem (hPS) cells with F7L6 initiates transcriptional programs similar to those observed during primitive streak formation and subsequent gastrulation in the mammalian embryo. This demonstrates that selective engagement and activation of FZD7 signaling is sufficient to promote mesendodermal differentiation of hPS cells.

Data availability

The RNA-seq and ChIP-seq data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE158121.

The following data sets were generated

Article and author information

Author details

  1. Diana Gumber

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0913-8001
  2. Myan Do

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5892-6859
  3. Neya Suresh Kumar

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Pooja R Sonavane

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christina C N Wu

    Department of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Luisjesus S Cruz

    Department of Biology, San Diego State University, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephanie Grainger

    Department of Biology, San Diego State University, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Dennis Carson

    Department of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Terry Gaasterland

    Scripps Institution of Oceanography, Scripps Genome Center, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Karl Willert

    Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States
    For correspondence
    kwillert@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8020-6804

Funding

National Institutes of Health (R35GM134961)

  • Karl Willert

National Institutes of Health (S10OD026929)

  • Karl Willert

National Cancer Institute (T32 CA067754,graduate student fellowship to Myan Do)

  • Myan Do

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

Reviewing Editor

  1. Yi Arial Zeng, Chinese Academy of Sciences, China

Publication history

  1. Received: September 13, 2020
  2. Accepted: December 16, 2020
  3. Accepted Manuscript published: December 17, 2020 (version 1)
  4. Version of Record published: December 24, 2020 (version 2)

Copyright

© 2020, Gumber 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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