Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin

Abstract
Data availability
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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

1. Telese F
2. Ma Q
3. Perez PM
4. Notani D
5. Oh S
6. Li W
7. Comoletti D
8. Ohgi KA
9. Taylor H
10. Rosenfeld MG
(2015) LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation
NCBI Gene Expression Omnibus, GSE66710.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66710

Article and author information

Author details

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.
Pauline Colombier

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Jianxin Hu

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-6664-8913
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.

"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

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.