Figure 5. Adult loss of TDP-43 in oligodendrocytes leads to hindlimb weakness.
(A) Mobp-iCreER allows Tardbp deletion at mature oligodendrocytes in the adult CNS. Schematics of CreER activation where tamoxifen is administered for five consecutive days at P90. Samples are collected for analyses 30 and 90 days after the last day of tamoxifen injection. (B) EGFP images from Mobp-TDP43-RCE Control and cKO at 30 and 90 days after Tardbp deletion. Yellow arrowhead indicates abnormal morphological changes in cKO oligodendrocytes at P90 +90. Scale bar = 25 μm. (C) Examples of limp tail and hindlimb clasping (yellow arrowheads) in Mobp-TDP43 cKO at P90 + 90 from Video 4. (D) Mobp-TDP43 cKO mice develop hindlimb paralysis at P90 + 90 (yellow arrowhead). (E) Experimental autoimmune encephalomyelitis (EAE) clinical score for Control and Mobp-TDP43 cKO mice. All Control mice at P90 + 90 exhibit no obvious changes in motor function whereas Mobp-TDP43 cKO mice develop limp tail and hindlimb weakness, which yield clinical scores between 2 and 2.5 (unpaired, two-tailed Student’s t-test, ***p value = 0.0002, n = 3). (F) Immunostaining for GFP and GFAP in the lumbar spinal cords of Mobp-TDP43-RCE Control and cKO at P90 + 90 shows global astrogliosis indicated by increased immunoreactivity of GFAP. Scale bar = 100 μm. (G) Quantification of mean GFAP fluorescence intensity (arbitrary unit; a.u.) shows a statistically significant increase in the mean intensity of GFAP in the spinal cord of Mobp-TDP43 cKO (unpaired, two-tailed Student’s t-test, **p value = 0.0096, n = 3).
Figure 5—figure supplement 1. Loss of TDP-43 in oligodendrocytes does not result in degeneration of spinal motor neurons.
