Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity
- University of California, San Francisco, United States
- University of Cambridge, United Kingdom
- Max Planck Institute of Experimental Medicine, Germany
- Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Germany
Figures
Figure 1 with 2 supplements
OL-Kir4.1 is upregulated during postnatal development and localized to peri-axonal spaces.
Kir4.1 ON protein levels were upregulated between age P40 and P140, whereas Kir5.1 protein levels did not change during aging (A–B). Note substantial loss of Kir4.1 protein in Olig2-cre driven Kcnj10…
Figure 1—figure supplement 1
Validation of OL-encoded Kcnj10 cKO efficiency
Kir4.1 channels were efficiently ablated from ON OLs in cKO-1 (n = 5) and cKO-2 (n = 4) mice versus control ONs (n = 5; A). One-way ANOVA with Tukey’s multiple comparisons test was performed in A; …
Figure 1—figure supplement 2
Early developmental changes in OL-encoded Kcnj10 loss-of-function
Kcnj10-deficient OPCs exhibited less BrdU incorporation in spinal cord tissue of P1 mice suggesting precocious exit from the cell cycle (ctrl: n = 4, cKO-1: n = 4; A). Likewise, purified and …
Figure 2 with 1 supplement
OL-Kir4.1 regulates early OL differentiation but is dispensable for myelination.
Early developmental loss of OL-Kcnj10 did not affect myelin sheath thickness or axon diameters in ONs from animals at P40 (210 axons from 4 control mice, 202 axons from 4 cKO-1 mice; A–C). Densities …
Figure 2—figure supplement 1
Early white matter changes in OL-encoded Kcnj10 loss-of-function
Intra-axonal mitochondria did not differ with respect to circularity and numbers per individual axon between ON tissue from control and cKO-1 mice (210 axons from 4 control mice, 202 axons from 4 …
Figure 3
OL-Kir4.1 controls motor performance and visual function in adult mice.
Mice lacking OL-Kir4.1 channels had increased mortality with survival rates of 96% in the control group (n = 29), 54% in cKO-1 (n = 13) and only 33% in cKO-2 (n = 9) mice at P180 (A). Log-rank …
Figure 4 with 2 supplements
OL-Kir4.1 has a critical role in WM integrity and long-term maintenance.
Myelin basic protein (Mbp) was decreased in ON lysates from cKO-1 (n = 4) mice versus controls (n = 4) at P180 (A). Mann-Whitney test was performed in A; *p≤0.05. Transmission electron microscopy …
Figure 4—figure supplement 1
Long-term white matter pathologies in chronic OL-encoded Kcnj10 loss of function
Note Kir4.1 protein levels were significantly reduced in ONs from cKO-1 mice at P180 (ctrl: n = 4, cKO-1: n = 4; A). Likewise, Kir4.1 protein levels were substantially decreased in spinal cord …
Figure 4—figure supplement 2
Long-term retinal changes in chronic OL-encoded Kcnj10 loss-of-function
Cartoon shows cross-section of inner retinal layers with glial cells expressing Kir4.1 (A); note that Kir4.1 immunoreactivity was increased in inner retinal layers of cKO-1 mice at P180 (B–C). Conver…
Figure 5 with 1 supplement
OL-Kir4.1 is dispensable for remyelination, but critical for long-term axon maintenance after WM demyelinating injury.
OL-Kir4.1 function was studied in short- (A–C) and long-term remyelination (D–F) after lysolecithin-induced focal demyelination to ventrolateral spinal WM tracts. Mice were euthanized and perfused …
Figure 5—figure supplement 1
Short- and long term remyelination efficiencies in chronic OL-Kcnj10 loss-of-function
No differences in g-ratios were observed in early (14dpl) and late (60dpl) remyelinating white matter lesions from control and cKO-1 mice.
Mann-Whitney tests were performed in A and B; p=0.34 (A and B). Data are presented as mean ±s.e.m in A and B.
Videos
Video 1
Ataxia and motor dysfunction are progressive symptoms in OL-Kcnj10 cKO mice.
Video shows gait ataxia in OL-Kcnj10 cKO mouse (left) as compared to littermate control (right) at P140.
Video 2
Seizures are common and progressive in adult OL-Kcnj10 cKO mice.
Video shows generalized seizure in OL-Kcnj10 cKO mouse at P140.
Video 3
Hind limb clasping is characteristic in adult OL-Kcnj10 cKO mice.
Video 3 shows hind limb clasping as typical sign of motor dysfunction in OL-Kcnj10 cKO mice compared to Video 4 without presence of hind limb clasping in a control mouse at P140.
Video 4
Hind limb clasping is not typical in normal adult mice.
Video 4 shows that hind limb clasping is not typical in an adult control mice.
Additional files
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Transparent reporting form
- https://doi.org/10.7554/eLife.36428.017
