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

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.

Data availability

Previously published ChIP-seq datasets available as BigWig files (Telese et al. 2015) were uploaded and visualized on the UCSC Genome Browser.

The following previously published data sets were used

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.

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.

Metrics

  • 1,216
    views
  • 167
    downloads
  • 8
    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. Denise M Poltavski
  2. Pauline Colombier
  3. Jianxin Hu
  4. Alicia Duron
  5. Brian L Black
  6. Takako Makita
(2019)
Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin
eLife 8:e42528.
https://doi.org/10.7554/eLife.42528

Share this article

https://doi.org/10.7554/eLife.42528

Further reading

    1. Developmental Biology
    Hanee Lee, Junsu Kang ... Junho Lee
    Research Article

    The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.

    1. Developmental Biology
    Alexandra V Bruter, Ekaterina A Varlamova ... Victor V Tatarskiy
    Research Article

    CDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have generated mice with the systemic inducible Cdk8 knockout on the background of Cdk19 constitutive knockout. Cdk8/19 double knockout (iDKO) males, but not single Cdk8 or Cdk19 KO, had an atrophic reproductive system and were infertile. The iDKO males lacked postmeiotic spermatids and spermatocytes after meiosis I pachytene. Testosterone levels were decreased whereas the amounts of the luteinizing hormone were unchanged. Single-cell RNA sequencing showed marked differences in the expression of steroidogenic genes (such as Cyp17a1, Star, and Fads) in Leydig cells concomitant with alterations in Sertoli cells and spermatocytes, and were likely associated with an impaired synthesis of steroids. Star and Fads were also downregulated in cultured Leydig cells after iDKO. The treatment of primary Leydig cell culture with a CDK8/19 inhibitor did not induce the same changes in gene expression as iDKO, and a prolonged treatment of mice with a CDK8/19 inhibitor did not affect the size of testes. iDKO, in contrast to the single knockouts or treatment with a CDK8/19 kinase inhibitor, led to depletion of cyclin C (CCNC), the binding partner of CDK8/19 that has been implicated in CDK8/19-independent functions. This suggests that the observed phenotype was likely mediated through kinase-independent activities of CDK8/19, such as CCNC stabilization.