1. Neuroscience

Remyelination alters the pattern of myelin in the cerebral cortex

  1. Jennifer Orthmann-Murphy  Is a corresponding author
  2. Cody L Call
  3. Gian C Molina-Castro
  4. Yu Chen Hsieh
  5. Matthew N Rasband  Is a corresponding author
  6. Peter A Calabresi
  7. Dwight E Bergles  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Johns Hopkins University School of Medicine, United States
  3. Massachusetts General Hospital, United States
  4. Baylor College of Medicine, United States
https://doi.org/10.7554/eLife.56621
Share this article
Cite this article
  1. Jennifer Orthmann-Murphy
  2. Cody L Call
  3. Gian C Molina-Castro
  4. Yu Chen Hsieh
  5. Matthew N Rasband
  6. Peter A Calabresi
  7. Dwight E Bergles
(2020)
Remyelination alters the pattern of myelin in the cerebral cortex
eLife 9:e56621.
https://doi.org/10.7554/eLife.56621
  2. Download BibTeX
  3. Download .RIS

Abstract

Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can be restored by regenerating oligodendrocytes from resident progenitors; however, it is not known whether regeneration restores the complex myelination patterns in cortical circuits. Here we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. These longitudinal studies revealed that the pattern of myelination in cortex changed dramatically after regeneration, as new oligodendrocytes were formed in different locations and new sheaths were often established along axon segments previously lacking myelin. Despite the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired in deeper cortical layers that experienced higher gliosis. Repeated reorganization of myelin patterns in MS may alter circuit function and contribute to cognitive decline.

Data availability

All data generated or analyzed in this study are included in the manuscript. Source code for analysis and figure generation are located at: https//github.com/clcall/Orthmann-Murphy_Call_etal_2020_Elife

Article and author information

Author details

  1. Jennifer Orthmann-Murphy

    Neurology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    Jennifer.Orthmann-Murphy@pennmedicine.upenn.edu
    Competing interests
    No competing interests declared.

  2. Cody L Call

    Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2254-4298

  3. Gian C Molina-Castro

    Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0700-4042

  4. Yu Chen Hsieh

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    No competing interests declared.

  5. Matthew N Rasband

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    rasband@bcm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8184-2477

  6. Peter A Calabresi

    Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    Peter A Calabresi, PI on grants to JHU from Biogen and Annexon and has received consulting fees for serving on scientific advisory boards for Biogen and Disarm Therapeutics.1147.

  7. Dwight E Bergles

    The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    dbergles@jhmi.edu
    Competing interests
    Dwight E Bergles, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7133-7378

Funding

Conrad N. Hilton Foundation

  • Jennifer Orthmann-Murphy

National Multiple Sclerosis Society

  • Jennifer Orthmann-Murphy

National Science Foundation (Graduate Research Fellowship)

  • Cody L Call

National Science Foundation (Graduate Research Fellowship)

  • Gian C Molina-Castro

National Institutes of Health (NS051509)

  • Dwight E Bergles

National Institutes of Health (NS050274)

  • Dwight E Bergles

National Institutes of Health (NS080153)

  • Dwight E Bergles

Dr. Miriam and Sheldon G Adelson Medical Research Foundation

  • Dwight E Bergles

National Multiple Sclerosis Society

  • Peter A Calabresi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Germany

Ethics

Animal experimentation: Animal experimentation: This study was performed in accordance with the recommendations provided in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments and procedures were approved by the Johns Hopkins Institutional Care and Use Committee (protocols: MO17M268, MO17M338). All surgery was performed under isoflurane anesthesia and every effort was made to minimize suffering.

Version history

  1. Received: March 4, 2020
  2. Accepted: May 22, 2020
  3. Accepted Manuscript published: May 27, 2020 (version 1)
  4. Version of Record published: June 12, 2020 (version 2)
  5. Version of Record updated: June 15, 2020 (version 3)

Copyright

© 2020, Orthmann-Murphy 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

  • 5,439
    views
  • 696
    downloads
  • 68
    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. Jennifer Orthmann-Murphy
  2. Cody L Call
  3. Gian C Molina-Castro
  4. Yu Chen Hsieh
  5. Matthew N Rasband
  6. Peter A Calabresi
  7. Dwight E Bergles
(2020)
Remyelination alters the pattern of myelin in the cerebral cortex
eLife 9:e56621.
https://doi.org/10.7554/eLife.56621

Share this article

https://doi.org/10.7554/eLife.56621

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Neuroscience

    KIS counteracts PTBP2 and regulates alternative exon usage in neurons

    Marcos Moreno-Aguilera, Alba M Neher ... Carme Gallego
    Research Article Updated

    Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.

    1. Genetics and Genomics
    2. Neuroscience

    Genetic Chimerism: Marmosets contain multitudes

    Kenneth Chiou, Noah Snyder-Mackler
    Insight

    Single-cell RNA sequencing reveals the extent to which marmosets carry genetically distinct cells from their siblings.

    1. Cell Biology
    2. Neuroscience

    Unraveling the link between Neuropathy Target Esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

    Mariana I Tsap, Andriy S Yatsenko ... Halyna R Shcherbata
    Research Article

    Mutations in Drosophila Swiss Cheese (SWS) gene or its vertebrate orthologue Neuropathy Target Esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well-established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain-barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.