Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity
- University of California, San Francisco, United States
- Max Planck Institute of Experimental Medicine, Germany
- University of Cambridge, United Kingdom
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.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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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.
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.
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Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity
eLife 7:e36428.
https://doi.org/10.7554/eLife.36428
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