1. Developmental Biology
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Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin

  1. Denise M Poltavski
  2. Pauline Colombier
  3. Jianxin Hu
  4. Alicia Duron
  5. Brian L Black
  6. Takako Makita  Is a corresponding author
  1. Children's Hospital Los Angeles, University of Southern California, United States
  2. University of California, San Francisco, United States
  3. Medical University of South Carolina, United States
Research Article
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Cite this article as: eLife 2019;8:e42528 doi: 10.7554/eLife.42528

Abstract

Developing neurons of the peripheral nervous system reach their targets via cues that support directional growth, a process known as axon guidance. In investigating how sympathetic axons reach the heart in mice, we discovered that a combination of guidance cues are employed in sequence to refine axon outgrowth, a process we term second-order guidance. Specifically, endothelin-1 induces sympathetic neurons expressing the receptor Ednra to project to the vena cavae leading to the heart. Endothelin signaling in turn induces expression of the repulsive receptor Plexin-A4, via induction of the transcription factor MEF2C. In the absence of endothelin or plexin signaling, sympathetic neurons misproject to incorrect competing vascular trajectories (the dorsal aorta and intercostal arteries). The same anatomical and physiological consequences occur in Ednra+/-; Plxna4+/- double heterozygotes, genetically confirming functional interaction. Second-order axon guidance therefore multiplexes a smaller number of guidance cues in sequential fashion, allowing precise refinement of axon trajectories.

Article and author information

Author details

  1. Denise M Poltavski

    Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Pauline Colombier

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jianxin Hu

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alicia Duron

    Darby Children's Research Institute, Medical University of South Carolina, Charleston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Brian L Black

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6664-8913
  6. Takako Makita

    Darby Children's Research Institute, Medical University of South Carolina, Charleston, United States
    For correspondence
    takako.makita@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5598-5690

Funding

National Institute of Neurological Disorders and Stroke (NS062901)

  • Takako Makita

National Institute of Neurological Disorders and Stroke (NS083265)

  • Takako Makita

National Heart, Lung, and Blood Institute (HL064658)

  • Brian L Black

National Heart, Lung, and Blood Institute (HL136182)

  • Brian L Black

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 experiments with animals complied with National Institute of Health guidelines and were reviewed and approved by the Children's Hospital Los Angeles (274-18), UCSF (AN171342) or MUSC (2018-00627) Institutional Animal Care and Use Committee.

Reviewing Editor

  1. David D Ginty, Harvard Medical School, United States

Publication history

  1. Received: October 3, 2018
  2. Accepted: February 6, 2019
  3. Accepted Manuscript published: February 8, 2019 (version 1)

Copyright

© 2019, Poltavski 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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