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.
-
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.
Reviewing Editor
- David D Ginty, Harvard Medical School, United States
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.
Version history
- Received: October 3, 2018
- Accepted: February 6, 2019
- Accepted Manuscript published: February 8, 2019 (version 1)
- Version of Record published: February 25, 2019 (version 2)
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
-
- 1,173
- views
-
- 160
- downloads
-
- 6
- 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)
Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin
eLife 8:e42528.
https://doi.org/10.7554/eLife.42528
Further reading
-
- Developmental Biology
Precise developmental timing control is essential for organism formation and function, but its mechanisms are unclear. In C. elegans, the microRNA lin-4 critically regulates developmental timing by post-transcriptionally downregulating the larval-stage-fate controller LIN-14. However, the mechanisms triggering the activation of lin-4 expression toward the end of the first larval stage remain unknown. We demonstrate that the transmembrane transcription factor MYRF-1 is necessary for lin-4 activation. MYRF-1 is initially localized on the cell membrane, and its increased cleavage and nuclear accumulation coincide with lin-4 expression timing. MYRF-1 regulates lin-4 expression cell-autonomously and hyperactive MYRF-1 can prematurely drive lin-4 expression in embryos and young first-stage larvae. The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter. Our findings identify a crucial link in understanding developmental timing regulation and establish MYRF-1 as a key regulator of lin-4 expression.
-
- Developmental Biology
- Structural Biology and Molecular Biophysics
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.
