eLife (Sep 2018)
Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity
- Lucas Schirmer,
- Wiebke Möbius,
- Chao Zhao,
- Andrés Cruz-Herranz,
- Lucile Ben Haim,
- Christian Cordano,
- Lawrence R Shiow,
- Kevin W Kelley,
- Boguslawa Sadowski,
- Garrett Timmons,
- Anne-Katrin Pröbstel,
- Jackie N Wright,
- Jung Hyung Sin,
- Michael Devereux,
- Daniel E Morrison,
- Sandra M Chang,
- Khalida Sabeur,
- Ari J Green,
- Klaus-Armin Nave,
- Robin JM Franklin,
- David H Rowitch
Affiliations
- Lucas Schirmer
- ORCiD
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States; Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
- Wiebke Möbius
- ORCiD
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
- Chao Zhao
- ORCiD
- Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
- Andrés Cruz-Herranz
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
- Lucile Ben Haim
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
- Christian Cordano
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
- Lawrence R Shiow
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
- Kevin W Kelley
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
- Boguslawa Sadowski
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
- Garrett Timmons
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
- Anne-Katrin Pröbstel
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
- Jackie N Wright
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
- Jung Hyung Sin
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
- Michael Devereux
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
- Daniel E Morrison
- Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
- Sandra M Chang
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
- Khalida Sabeur
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States
- Ari J Green
- Department of Neurology, University of California, San Francisco, San Francisco, United States; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States; Department of Ophthalmology, University of California, San Francisco, San Francisco, United States
- Klaus-Armin Nave
- ORCiD
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
- Robin JM Franklin
- Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
- David H Rowitch
- ORCiD
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United States; Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Neurosurgery, University of California, San Francisco, San Francisco, United States
- DOI
- https://doi.org/10.7554/eLife.36428
- Journal volume & issue
-
Vol. 7
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 axonal function and integrity during adulthood and after WM injury.
Keywords
