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SIRT6 Negatively Regulates Schwann Cells Dedifferentiation via Targeting c-Jun During Wallerian Degeneration After Peripheral Nerve Injury

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Abstract

Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Previous studies have been reported a pro-regenerative role of SIRT6 in central nervous system injury. However, the role of SIRT6 in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of SIRT6 steering Schwann cell dedifferentiation during Wallerian degeneration in injured peripheral nerve. Herein, we first examined the expression pattern of SIRT6 after peripheral nerve injury. Using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that SIRT6 inhibitor accelerates Schwann cell dedifferentiation as well as axonal and myelin degeneration, while SIRT6 activator attenuates this process. Moreover, in an in vitro Schwann cell dedifferentiation model, we found SIRT6 inhibitor promotes Schwann cell dedifferentiation through upregulating the expression of c-Jun. In addition, downregulation of c-Jun reverse the effects of SIRT6 inhibition on the Schwann cells dedifferentiation and axonal and myelin degeneration. In summary, we first described SIRT6 acts as a negative regulator for Schwann cells dedifferentiation during Wallerian degeneration and c-Jun worked as a direct downstream partner of SIRT6 in injured peripheral nerve.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China, Nos.82071386, 81870982&81571182; National Key Basic Research Program of China, No. 2014CB542202; the Program for Changjiang Scholars and Innovative Research Team in University of China, No. IRT-16R37; Key Research & Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory of China, No. 2018GZR110104008; Research Grant of Guangdong Province Key Laboratory of Psychiatric Disorders of China, No. N201904; and Natural Science Foundation of Guangdong Province of China, No. 2017A030312009.

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Authors and Affiliations

  1. Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Ying Zou, Jiaqi Zhang, Jingmin Liu, Jiawei Xu, Lanya Fu, Xinrui Ma, Yizhou Xu, Shuyi Xu, Xianghai Wang & Jiasong Guo

  2. Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, 510515, China

    Ying Zou, Jiaqi Zhang, Jingmin Liu, Jiawei Xu, Lanya Fu, Xinrui Ma, Yizhou Xu, Shuyi Xu, Xianghai Wang & Jiasong Guo

  3. Department of Spine Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Yizhou Xu & Jiasong Guo

  4. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510700, China

    Xianghai Wang & Jiasong Guo

  5. Key Laboratory of Mental Health of the Ministry of EducationGuangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, 510515, China

    Jiasong Guo

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  1. Ying Zou
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Contributions

Jiasong Guo and Ying Zou designed the research and wrote the manuscript. Ying Zou and Jiaqi Zhang performed experiments with Jingmin Liu, Jiawei Xu, Lanya Fu, and Xianghai Wang assistance. Xinrui Ma, Yizhou Xu, and Shuyi Xu analyzed the data. Jiasong Guo and Jiaqi Zhang critically reviewed and revised the manuscript.

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Correspondence to Jiasong Guo.

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All animal procedures were carried out with the approval of the Southern Medical University Animal Care and Use Committee in accordance with the guidelines for the ethical treatments of animals.

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Zou, Y., Zhang, J., Liu, J. et al. SIRT6 Negatively Regulates Schwann Cells Dedifferentiation via Targeting c-Jun During Wallerian Degeneration After Peripheral Nerve Injury. Mol Neurobiol 59, 429–444 (2022). https://doi.org/10.1007/s12035-021-02607-3

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