Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk

  1. Lin Grimm
  2. Hiroyuki Nakajima
  3. Smrita Chaudhury
  4. Neil I Bower
  5. Kazuhide S Okuda
  6. Andrew G Cox
  7. Natasha L Harvey
  8. Katarzyna Koltowska
  9. Naoki Mochizuki
  10. Benjamin M Hogan  Is a corresponding author
  1. University of Queensland, Australia
  2. National Cerebral and Cardiovascular Center Research Institute, Japan
  3. Peter MacCallum Cancer Centre, Australia
  4. University of South Australia, Australia
  5. Uppsala University, Sweden

Abstract

Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. Hippo pathway and effectors Yap and Taz promote organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that Yap1 displays dynamic changes in lymphatic progenitors and is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear Yap1 in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Lin Grimm

    Institute of Molecular Biosciences, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Hiroyuki Nakajima

    Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Smrita Chaudhury

    Institute of Molecular Biosciences, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Neil I Bower

    Institute of Molecular Biosciences, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Kazuhide S Okuda

    Institute of Molecular Biosciences, University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrew G Cox

    Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4189-9422
  7. Natasha L Harvey

    Centre for Cancer Biology, University of South Australia, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Katarzyna Koltowska

    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  9. Naoki Mochizuki

    Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3938-9602
  10. Benjamin M Hogan

    Institute of Molecular Biosciences, University of Queensland, Brisbane, Australia
    For correspondence
    b.hogan@imb.uq.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0651-7065

Funding

National Heart Foundation of Australia (1083811)

  • Benjamin M Hogan

National Health and Medical Research Council (1155221)

  • Benjamin M Hogan

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

Ethics

Animal experimentation: All zebrafish work was conducted in accordance with the guidelines of the animal ethic committee guidelines at the University of Queensland and of the National Cerebral and Cardiovascular Center (No.14005 and No.15010).

Reviewing Editor

  1. Holger Gerhardt, Max Delbrück Centre for Molecular Medicine, Germany

Publication history

  1. Received: October 16, 2018
  2. Accepted: April 28, 2019
  3. Accepted Manuscript published: April 30, 2019 (version 1)
  4. Version of Record published: May 14, 2019 (version 2)

Copyright

© 2019, Grimm 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. Lin Grimm
  2. Hiroyuki Nakajima
  3. Smrita Chaudhury
  4. Neil I Bower
  5. Kazuhide S Okuda
  6. Andrew G Cox
  7. Natasha L Harvey
  8. Katarzyna Koltowska
  9. Naoki Mochizuki
  10. Benjamin M Hogan
(2019)
Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk
eLife 8:e42881.
https://doi.org/10.7554/eLife.42881

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