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GSK3β Promotes the Differentiation of Oligodendrocyte Precursor Cells via β-Catenin-Mediated Transcriptional Regulation

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Abstract

Oligodendrocytes are generated by the differentiation and maturation of oligodendrocyte precursor cells (OPCs). The failure of OPC differentiation is a major cause of demyelinating diseases; thus, identifying the molecular mechanisms that affect OPC differentiation is critical for understanding the myelination process and repairing after demyelination. Although prevailing evidence shows that OPC differentiation is a highly coordinated process controlled by multiple extrinsic and intrinsic factors, such as growth factors, axon signals, and transcription factors, the intracellular signaling in OPC differentiation is still unclear. Here, we showed that glycogen synthase kinase 3β (GSK3β) is an essential positive modulator of OPC differentiation. Both pharmacologic inhibition and knockdown of GSK3β remarkably suppressed OPC differentiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays and Ki67 staining showed that the effect of GSK3β on OPC differentiation was not via cell death. Conversely, activated GSK3β was sufficient to promote OPC differentiation. Our results also demonstrated that the transcription of myelin genes was regulated by GSK3β inhibition, accompanying accumulated nuclear β-catenin, and reduced the expression of transcriptional factors that are relevant to the expression of myelin genes. Taken together, our study identified GSK3β as a profound positive regulator of OPC differentiation, suggesting that GSK3β may contribute to the inefficient regeneration of oligodendrocytes and myelin repair after demyelination.

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Acknowledgements

We thank Dr. Yi Rao (Beijing University, Beijing, China) for kindly providing the GSK3β-S9A plasmid. We are grateful for the helpful advice from the members of the Shen lab. We thank Dr. Iain C. Bruce for his help during the preparation of the manuscript. This work was supported by grants from the National Basic Research Program (973) of the Ministry of Science and Technology of China (2009CB941400, 2011CB504400, and 2013CB531300), the National Foundation of Natural Science of China (31260243, 31200818,31271148, 31060140, 31071879), the Zhejiang Provincial Foundation of Natural Science (LY12C09002), the Program for New Century Excellent Talents in University from the Ministry of Education of China for Ying Shen (NCET-07-0751) and Yin Wang, and the Fundament Research Funds for the Central University (2011FZA7002 and 2013QNA7007).

Conflict of Interest

All authors indicate that they do not have the financial relationship with the organizations that sponsored the current research.

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Authors and Affiliations

  1. Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China

    Liang Zhou, Chong-Yu Shao, Si-min Xu, Ya-Jun Xie, Lin Zhou & Ying Shen

  2. Institute of Developmental and Regenerative Biology, College of Life and Environmental Science, Hangzhou Normal University, Hangzhou, 310029, People’s Republic of China

    Peng Teng & Mengsheng Qiu

  3. Department of Neurobiology, Center of Scientific Technology, Cranial Cerebral Disease Lab, Ningxia Medical University, Yinchuan, People’s Republic of China

    Jiao Ma & Yin Wang

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  1. Liang Zhou
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  2. Chong-Yu Shao
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  3. Si-min Xu
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  9. Mengsheng Qiu
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Correspondence to Yin Wang, Mengsheng Qiu or Ying Shen.

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Liang Zhou and Chong-Yu Shao contributed equally to this work.

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Figure S1

Effects of AR-A on OPC differentiation are not mediated by T3. (A) Representative images of OLs stained with antibodies to MBP (red) and Olig2 (green) in the control (Ctrl) and AR-A groups. Cells were exposed to AR-A for 7 days without T3. Scale bar: 40 μm. (B) The percentages of MBP+ OLs in Olig2+ cells were 49 ± 3 % (Ctrl) and 23 ± 2 % (AR-A). (GIF 196 kb)

High resolution image (TIFF 1692 kb)

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Zhou, L., Shao, CY., Xu, Sm. et al. GSK3β Promotes the Differentiation of Oligodendrocyte Precursor Cells via β-Catenin-Mediated Transcriptional Regulation. Mol Neurobiol 50, 507–519 (2014). https://doi.org/10.1007/s12035-014-8678-9

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