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

Version 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.

Metrics

  • 8,107
    views
  • 1,194
    downloads
  • 102
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.36953

Further reading

    1. Developmental Biology
    Thierry Gilbert, Camille Gorlt ... Andreas Merdes
    Research Article Updated

    Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human NINEIN gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts, whereas the number of osteoblasts remains unaffected. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.

    1. Cell Biology
    2. Developmental Biology
    Nicolas Loyer, Elizabeth KJ Hogg ... Jens Januschke
    Research Article

    The generation of distinct cell fates during development depends on asymmetric cell division of progenitor cells. In the central and peripheral nervous system of Drosophila, progenitor cells respectively called neuroblasts or sensory organ precursors use PAR polarity during mitosis to control cell fate determination in their daughter cells. How polarity and the cell cycle are coupled, and how the cell cycle machinery regulates PAR protein function and cell fate determination is poorly understood. Here, we generate an analog sensitive allele of CDK1 and reveal that its partial inhibition weakens but does not abolish apical polarity in embryonic and larval neuroblasts and leads to defects in polarisation of fate determinants. We describe a novel in vivo phosphorylation of Bazooka, the Drosophila homolog of PAR-3, on Serine180, a consensus CDK phosphorylation site. In some tissular contexts, phosphorylation of Serine180 occurs in asymmetrically dividing cells but not in their symmetrically dividing neighbours. In neuroblasts, Serine180 phosphomutants disrupt the timing of basal polarisation. Serine180 phosphomutants also affect the specification and binary cell fate determination of sensory organ precursors as well as Baz localisation during their asymmetric cell divisions. Finally, we show that CDK1 phosphorylates Serine-S180 and an equivalent Serine on human PAR-3 in vitro.