Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates

  1. Benjamin Mattes
  2. Yonglong Dang
  3. Gediminas Greicius
  4. Lilian Tamara Kaufmann
  5. Benedikt Prunsche
  6. Jakob Rosenbauer
  7. Johannes Stegmaier
  8. Ralf Mikut
  9. Suat Özbek
  10. Gerd Ulrich Nienhaus
  11. Alexander Schug
  12. David M Virshup
  13. Steffen Scholpp  Is a corresponding author
  1. University of Exeter, United Kingdom
  2. Karlsruhe Institute of Technology, Germany
  3. Duke-NUS Medical School, Singapore
  4. University Hospital Heidelberg, Germany
  5. John von Neumann Institute for Computing, Germany
  6. University of Heidelberg, Germany

Abstract

Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/PCP autocrine signaling controls the emergence of cytonemes, and that cytonemes subsequently control paracrine Wnt/β-catenin signal activation. Upon binding of the Wnt family member Wnt8a, the receptor tyrosine kinase Ror2 gets activated. Ror2/PCP signaling leads to induction of cytonemes, which mediate transport of Wnt8a to neighboring cells. In the Wnt receiving cells, Wnt8a on cytonemes triggers Wnt/β-catenin-dependent gene transcription and proliferation. We show that cytoneme-based Wnt transport operates in diverse processes, including zebrafish development, the murine intestinal crypt, and human cancer organoids, demonstrating that Wnt transport by cytonemes and its control via the Ror2 pathway is highly conserved in vertebrates.

Data availability

All of the data supporting this paper is available via the Dryad repository (https://dx.doi.org/10.5061/dryad.38q5pc1)

The following data sets were generated

Article and author information

Author details

  1. Benjamin Mattes

    Living Systems Institute, School of Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5286-9347
  2. Yonglong Dang

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Gediminas Greicius

    Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Lilian Tamara Kaufmann

    Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Benedikt Prunsche

    Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Jakob Rosenbauer

    Jülich Supercomputing Centre, Forschungszentrum Jülich, John von Neumann Institute for Computing, Jülich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Johannes Stegmaier

    Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4072-3759
  8. Ralf Mikut

    Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Suat Özbek

    Centre of Organismal Studies, University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Gerd Ulrich Nienhaus

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5027-3192
  11. Alexander Schug

    Institute for Automation and Applied Informatics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. David M Virshup

    Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6976-850X
  13. Steffen Scholpp

    Living Systems Institute, School of Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, United Kingdom
    For correspondence
    s.scholpp@exeter.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4903-9657

Funding

Living Systems Institute (Start-up)

  • Steffen Scholpp

Boehringer Ingelheim Fonds (Exploration)

  • Steffen Scholpp

Deutsche Forschungsgemeinschaft (Scho847-5)

  • Steffen Scholpp

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

Reviewing Editor

  1. Thomas B Kornberg, University of California, San Francisco, United States

Publication history

  1. Received: March 24, 2018
  2. Accepted: July 16, 2018
  3. Accepted Manuscript published: July 31, 2018 (version 1)
  4. Version of Record published: August 10, 2018 (version 2)

Copyright

© 2018, Mattes 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. Benjamin Mattes
  2. Yonglong Dang
  3. Gediminas Greicius
  4. Lilian Tamara Kaufmann
  5. Benedikt Prunsche
  6. Jakob Rosenbauer
  7. Johannes Stegmaier
  8. Ralf Mikut
  9. Suat Özbek
  10. Gerd Ulrich Nienhaus
  11. Alexander Schug
  12. David M Virshup
  13. Steffen Scholpp
(2018)
Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates
eLife 7:e36953.
https://doi.org/10.7554/eLife.36953

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