Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin
- Children's Hospital Los Angeles, University of Southern California, United States
- University of California, San Francisco, United States
- 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.
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LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory FormationNCBI Gene Expression Omnibus, GSE66710.
Article and author information
Author details
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.
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Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin
eLife 8:e42528.
https://doi.org/10.7554/eLife.42528
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