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MARK2 Rescues Nogo-66-Induced Inhibition of Neurite Outgrowth via Regulating Microtubule-Associated Proteins in Neurons In Vitro

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Abstract

The ability of neurons in the adult mammalian central nervous system (CNS) to regenerate after injury is limited by inhibitors in CNS myelin. Nogo-66 is the most important myelin inhibitor but the mechanisms of Nogo-66 inhibition of neurite outgrowth remain poorly understood. Particularly, the relationship between Nogo-66 and microtubule-affinity regulating kinase 2 (MARK2) has not been examined. This study investigated the role of MARK2 in Nogo-66 inhibition and the function of MARK2 in neurite elongation in neurons in vitro. MARK2 and phosphorylated MARK2 at Ser212 (p-Ser212) alterations in Neuro 2a cells were assessed at different Nogo-66 exposure times; the relationships between MARK2 and microtubule-associated proteins (MAPs) were determined via the overexpression or interference of MARK2. Our study reports that Nogo-66 inhibited the expression of total MARK2 but also reduced Ser212 phosphorylation of MARK2, whereas levels of MAP1-b and tau varied depending on MARK2 overexpression or reduced expression. Furthermore, MARK2 increased the proportion of tyrosinated α-tubulin, thereby disrupting the stability of tubulin, most likely affecting axonal growth. In line with these results, overexpression of MARK2 promoted neurite elongation and therefore is able to rescue the inhibitory effect of Nogo-66 on neurite growth. In conclusion, the intracellular PKB/MARK2/MAPs/α-tubulin pathway appears to be essential for neurite elongation in neurons in vitro. These results suggest a critical role for MARK2 in overcoming Nogo-66-induced inhibition of axon outgrowth in neurons. Pharmacological activators of MARK2 may be applicable to promote successful axonal outgrowth following many types of CNS injuries.

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Acknowledgments

We would like to thank Professor Li Honglian for technical support.

Funding

This research was funded by the National Natural Science Foundation of China (81371380).

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Authors and Affiliations

  1. Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Street, Wuhan, Hubei, 430022, China

    Yu-Chao Zuo, Nan-Xiang Xiong, Hua Yu, Yi-Zhi Huang & Hong-Yang Zhao

  2. Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Yu-Chao Zuo

  3. Section of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road, Wuhan, Hubei, 430030, China

    Jian-Ying Shen

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  1. Yu-Chao Zuo
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  3. Jian-Ying Shen
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  4. Hua Yu
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  5. Yi-Zhi Huang
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Correspondence to Nan-Xiang Xiong or Hong-Yang Zhao.

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Yu-Chao Zuo and Nan-Xiang Xiong contributed equally to this work.

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Zuo, YC., Xiong, NX., Shen, JY. et al. MARK2 Rescues Nogo-66-Induced Inhibition of Neurite Outgrowth via Regulating Microtubule-Associated Proteins in Neurons In Vitro. Neurochem Res 41, 2958–2968 (2016). https://doi.org/10.1007/s11064-016-2016-8

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  • DOI: https://doi.org/10.1007/s11064-016-2016-8

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