1. Neuroscience
Download icon

Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity

Research Article
  • Cited 0
  • Views 489
  • Annotations
Cite as: eLife 2018;7:e36428 doi: 10.7554/eLife.36428

Abstract

Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of KCNJ10, which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K+ removal. Conditional knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axon function and integrity during adulthood and after WM injury.

Article and author information

Author details

  1. Lucas Schirmer

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    Lucas Schirmer, filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1).
    ORCID icon 0000-0001-7142-4116
  2. Wiebke Möbius

    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon 0000-0002-2902-7165
  3. Chao Zhao

    Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon 0000-0003-1144-1621
  4. Andrés Cruz-Herranz

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Lucile Ben Haim

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  6. Christian Cordano

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  7. Lawrence R Shiow

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  8. Kevin W Kelley

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Boguslawa Sadowski

    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Competing interests
    No competing interests declared.
  10. Garrett Timmons

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  11. Anne-Katrin Pröbstel

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  12. Jackie N Wright

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  13. Jung Hyung Sin

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  14. Michael Devereux

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  15. Daniel E Morrison

    Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  16. Sandra M Chang

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  17. Khalida Sabeur

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  18. Ari Green

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  19. Klaus-Armin Nave

    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
    Competing interests
    Klaus-Armin Nave, Reviewing editor, eLife.
    ORCID icon 0000-0001-8724-9666
  20. Robin JM Franklin

    Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  21. David H Rowitch

    Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    dhr25@medschl.cam.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon 0000-0002-0079-0060

Funding

National Multiple Sclerosis Society (FG-1607-25111)

  • Lucas Schirmer

European Commission (ERC advanced grant - AxoGLIA)

  • Klaus-Armin Nave

National Multiple Sclerosis Society (FG-20102-A-1)

  • Andrés Cruz-Herranz

Deutsche Forschungsgemeinschaft (EXC171)

  • Wiebke Möbius
  • Klaus-Armin Nave

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P300PB_177927)

  • Anne-Katrin Pröbstel

European Commission (ERC advanced grant - MyeliNANO)

  • Klaus-Armin Nave

Deutsche Forschungsgemeinschaft (TR43)

  • Wiebke Möbius

Deutsche Forschungsgemeinschaft (SCHI 1330/1-1)

  • Lucas Schirmer

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P2SKP3_164938/1)

  • Anne-Katrin Pröbstel

Associazione Italiana Sclerosi Multipla (2013/B/4)

  • Christian Cordano

Multiple Sclerosis Society (Project grant)

  • Robin JM Franklin

Wellcome (Senior investigator grant)

  • David H Rowitch

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Collaborative research grant)

  • Klaus-Armin Nave
  • Robin JM Franklin
  • David H Rowitch

National Institutes of Health (NS040511)

  • David H Rowitch

California Institute of Regenerative Medicine (Medical Scientist Training Program)

  • Kevin W Kelley

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 mouse strains were maintained at the University of California, San Francisco (UCSF) specific pathogen-free animal facility under protocol number AN110094. All animal protocols were approved by and in accordance with the guidelines established by the Institutional Animal Care and Use Committee and Laboratory Animal Resource Center.

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Publication history

  1. Received: March 7, 2018
  2. Accepted: September 9, 2018
  3. Accepted Manuscript published: September 11, 2018 (version 1)

Copyright

© 2018, Schirmer 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

  • 489
    Page views
  • 139
    Downloads
  • 0
    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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)