Figure 4. Oligodendrocytes without TDP-43 undergo aberrant morphological changes and exhibit aberrant wrapping of nonaxonal structures.

(A) Representative images of single oligodendrocytes from Control (Mobp-EGFP) and Mobp-TDP43 KO at P180. Scale bar = 25 μm. (B) Examples of abnormal structures formed by TDP-43 KO oligodendrocytes. Yellow arrowheads point to abnormal structures for each category. Scale bar = 10 μm. (C) Immunostaining of GFP and NeuN in Mobp-TDP43-RCE KO shows a formation of basket-like EGFP+ structure that ensheaths NeuN+ neuronal cell body (yellow arrowhead). Blue arrowhead points to a tubing-like EGFP+ structure. Scale bar = 25 μm. (D) Optical serial sections representing 1.5 μm increments in the z-axis showing wrapping of a NeuN+ neuronal soma by EGFP+ oligodendrocyte processes in Mobp-TDP43-RCE KO at P180. Scale bar = 10 μm. (E) Immunostaining of GFP and GS-Isolectin in Mog-TDP43-RCE KO at P180 shows tight wrapping of the blood vessels by EGFP+ oligodendrocyte processes (blue arrowheads). Scale bar = 50 μm. (F) In vivo imaging of Mobp-TDP43-RCE KO mouse after retro-orbital injection of 70 kDa dextran–rhodamine shows wrapping of the capillaries by EGFP+TDP-43 KO oligodendrocyte. Blue arrows show sites of wrapping. Scale bar = 25 μm.

Figure 4—figure supplement 1. Oligodendrocytes undergo progressive morphological changes with loss of TDP-43.

EGFP images from the motor cortex of Mobp-TDP43-RCE and Mog-TDP43-RCE mouse lines at P30, P90, and P180 show progressive changes in EGFP+ oligodendrocyte morphology where there is no difference at P30 and dramatic abnormality by P180 (yellow arrowheads). Scale bar = 50 μm.

Figure 4—figure supplement 2. Abnormal oligodendrocyte morphological phenotype due to loss of TDP-43 is persistent throughout the CNS.

(A) Tiled coronal mouse brain section to show that hypertrophic oligodendrocyte changes can be seen throughout the brain at P180. (B) EGFP immunoreactivity shows that abnormal oligodendrocyte morphologies can be seen in the optic nerve and spinal cord.

Figure 4—figure supplement 3. Longitudinal two-photon in vivo imaging of Mobp-TDP43 KO oligodendrocytes across 14 days.

Figure 4—figure supplement 4. Aberrant wrapping of non-axonal structures is prevalent in Mobp-TDP43 KO brains.

(A) Motor cortex of P180 Mobp-TDP43 KO shows that aberrant EGFP structures can be readily identified. Blue arrowheads indicate tubing-like structures that resemble blood vessel wrapping and yellow arrowheads indicate neuronal wrapping. (B) Quantification of the number of abnormal wrapping of blood vessels (blue) and neuronal soma (yellow) in a given field of view (FOV, 450 × 450 × 35 µm).

Figure 4—figure supplement 5. Loss of TDP-43 in oligodendrocytes potentially contributes to the disruption of blood-brain barrier (BBB) and de-differentiation of oligodendrocytes.

(A) Immunostaining for aquaporin four shows that EGFP+ wrapping displaces aquaporin 4 + astrocyte endfeet (yellow arrowheads). (B) Ki-67+NG2− oligodendrocytes can be found in P180 Mobp-TDP43 KO.