Dynamic early clusters of nodal proteins contribute to node of Ranvier assembly during myelination of peripheral neurons

  1. Elise LV Malavasi
  2. Aniket Ghosh
  3. Daniel G Booth
  4. Michele Zagnoni
  5. Diane L Sherman
  6. Peter J Brophy  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. University of Nottingham, United Kingdom
  3. University of Strathclyde, United Kingdom

Abstract

Voltage-gated sodium channels cluster in macromolecular complexes at nodes of Ranvier to promote rapid nerve impulse conduction in vertebrate nerves. Node assembly in peripheral nerves is thought to be initiated at heminodes at the extremities of myelinating Schwann cells and fusion of heminodes results in the establishment of nodes. Here we show that assembly of 'early clusters' of nodal proteins in the murine axonal membrane precedes heminode formation. The Neurofascin (Nfasc) proteins are essential for node assembly, and the formation of early clusters also requires neuronal Nfasc. Early clusters are mobile and their proteins are dynamically recruited by lateral diffusion. They can undergo fusion not only with each other but also with heminodes thus contributing to the development of nodes in peripheral axons. The formation of early clusters constitutes the earliest stage in peripheral node assembly and expands the repertoire of strategies that have evolved to establish these essential structures.

Data availability

All source data files have been provided

Article and author information

Author details

  1. Elise LV Malavasi

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2240-0553
  2. Aniket Ghosh

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3771-6390
  3. Daniel G Booth

    Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Michele Zagnoni

    Centre for Microsystems and Photonics, Electronic and Electrical Engineering, University of Strathclyde, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Diane L Sherman

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3104-6656
  6. Peter J Brophy

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    peter.brophy@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0262-9545

Funding

Wellcome Trust (107008)

  • Peter J Brophy

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 animal work conformed to UK legislation (Scientific Procedures) Act 1986 and to the University of Edinburgh Ethical Review policy and was performed under Project Licence No. P0F4A25E9 from the Animals in Science Regulation Unit of the UK Home Office.

Reviewing Editor

  1. Moses V Chao, New York University Langone Medical Center, United States

Version history

  1. Received: March 4, 2021
  2. Accepted: July 7, 2021
  3. Accepted Manuscript published: July 9, 2021 (version 1)
  4. Version of Record published: July 19, 2021 (version 2)

Copyright

© 2021, Malavasi 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

  • 1,127
    Page views
  • 151
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Elise LV Malavasi
  2. Aniket Ghosh
  3. Daniel G Booth
  4. Michele Zagnoni
  5. Diane L Sherman
  6. Peter J Brophy
(2021)
Dynamic early clusters of nodal proteins contribute to node of Ranvier assembly during myelination of peripheral neurons
eLife 10:e68089.
https://doi.org/10.7554/eLife.68089

Further reading

    1. Chromosomes and Gene Expression
    2. Neuroscience
    Alan E Murphy, Nurun Fancy, Nathan Skene
    Research Article

    Mathys et al. conducted the first single-nucleus RNA-seq (snRNA-seq) study of Alzheimer’s disease (AD) (Mathys et al., 2019). With bulk RNA-seq, changes in gene expression across cell types can be lost, potentially masking the differentially expressed genes (DEGs) across different cell types. Through the use of single-cell techniques, the authors benefitted from increased resolution with the potential to uncover cell type-specific DEGs in AD for the first time. However, there were limitations in both their data processing and quality control and their differential expression analysis. Here, we correct these issues and use best-practice approaches to snRNA-seq differential expression, resulting in 549 times fewer DEGs at a false discovery rate of 0.05. Thus, this study highlights the impact of quality control and differential analysis methods on the discovery of disease-associated genes and aims to refocus the AD research field away from spuriously identified genes.

    1. Neuroscience
    Josue Haubrich, Karim Nader
    Research Article

    The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using c-fos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.