Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling
Zhixiong Liu, … , Zhanxiang Wang, Liang Zhang
Zhixiong Liu, … , Zhanxiang Wang, Liang Zhang
Published February 10, 2022
Citation Information: J Clin Invest. 2022;132(7):e155096. https://doi.org/10.1172/JCI155096.
View: Text | PDF
Research Article Cell biology Neuroscience

Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling

Abstract

Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.

Authors

Zhixiong Liu, Minbiao Yan, Wanying Lei, Rencai Jiang, Wenxiu Dai, Jialin Chen, Chaomeng Wang, Li Li, Mei Wu, Ximing Nian, Daopeng Li, Di Sun, Xiaoqi Lv, Chaoying Wang, Changchuan Xie, Luming Yao, Caiming Wu, Jin Hu, Naian Xiao, Wei Mo, Zhanxiang Wang, Liang Zhang

×

Figure 5

Sec13 is critical for adult remyelination after demyelination.

Options: View larger image (or click on image) Download as PowerPoint
Sec13 is critical for adult remyelination after demyelination. (A) Diagr...
(A) Diagram showing tamoxifen administration to 8-week-old control (Sec13 fl/fl) and Sec13-iKO (Sec13 fl/fl NG2-CreERT) mice followed by LPC injection 7 days later. (B) Immunostaining for Olig2 and Sec13 in the corpus callosum of control and Sec13-iKO mice at 14 dpl. Arrowheads indicate Olig2+ cells. Scale bars: 50 μm. (C) Quantification of Sec13+Olig2+ cells as a percentage of total Olig2+ cells in the corpus callosum at 14 dpl (n = 3 control and n = 3 mutant animals). (D) Immunostaining for IBA1 and MBP in corpus callosum lesions of control and Sec13-iKO mice at 14 dpl. Scale bars: 200 μm. (E and F) Quantification of MBP+ volume (E) and lesion area (F) in corpus callosum lesions of control and Sec13-iKO mice at 14 dpl (n = 3 control and n = 3 mutant animals). (G) Immunostaining for MBP in spinal cord lesions of control and Sec13-iKO mice at 14 dpl and 21 dpl. Scale bars: 50 μm. (H and I) Immunostaining (H) and quantification (I) of CC1+ cells in spinal cord lesions of control and Sec13-iKO mice at 14 dpl (n = 3 control and 3 mutant animals). Scale bar: 50 μm. (J) Electron microscopic images of LPC-induced lesions in spinal cords from control and Sec13-iKO mice at 14 dpl. Scale bars: 2 μm. (K) Quantification of remyelinated axons in LPC-induced lesions in spinal cords from control and Sec13-iKO mice at 14 dpl (n = 3 control and n = 3 mutant animals). (L) Myelin g-ratios in LPC-induced lesions of spinal cord from control and Sec13-iKO mice at 14 dpl. Data represent the mean ± SD. **P < 0.01 and ***P < 0.001, by 2-tailed, unpaired Student’s t test.