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The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration

BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no th...

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Autores principales: Xu, Jinghui, Zhang, Bin, Cai, Jieyi, Peng, Qianqian, Hu, Junxia, Askar, Parizat, Shangguan, Jianghong, Su, Wenfeng, Zhu, Changlai, Sun, Hualin, Zhou, Songlin, Chen, Gang, Yang, Xiaoming, Gu, Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291779/
https://www.ncbi.nlm.nih.gov/pubmed/37365519
http://dx.doi.org/10.1186/s10020-023-00667-w
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author Xu, Jinghui
Zhang, Bin
Cai, Jieyi
Peng, Qianqian
Hu, Junxia
Askar, Parizat
Shangguan, Jianghong
Su, Wenfeng
Zhu, Changlai
Sun, Hualin
Zhou, Songlin
Chen, Gang
Yang, Xiaoming
Gu, Yun
author_facet Xu, Jinghui
Zhang, Bin
Cai, Jieyi
Peng, Qianqian
Hu, Junxia
Askar, Parizat
Shangguan, Jianghong
Su, Wenfeng
Zhu, Changlai
Sun, Hualin
Zhou, Songlin
Chen, Gang
Yang, Xiaoming
Gu, Yun
author_sort Xu, Jinghui
collection PubMed
description BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00667-w.
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spelling pubmed-102917792023-06-27 The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration Xu, Jinghui Zhang, Bin Cai, Jieyi Peng, Qianqian Hu, Junxia Askar, Parizat Shangguan, Jianghong Su, Wenfeng Zhu, Changlai Sun, Hualin Zhou, Songlin Chen, Gang Yang, Xiaoming Gu, Yun Mol Med Research Article BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00667-w. BioMed Central 2023-06-26 /pmc/articles/PMC10291779/ /pubmed/37365519 http://dx.doi.org/10.1186/s10020-023-00667-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Xu, Jinghui
Zhang, Bin
Cai, Jieyi
Peng, Qianqian
Hu, Junxia
Askar, Parizat
Shangguan, Jianghong
Su, Wenfeng
Zhu, Changlai
Sun, Hualin
Zhou, Songlin
Chen, Gang
Yang, Xiaoming
Gu, Yun
The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
title The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
title_full The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
title_fullStr The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
title_full_unstemmed The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
title_short The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
title_sort transcription factor stat-1 is essential for schwann cell differentiation, myelination and myelin sheath regeneration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291779/
https://www.ncbi.nlm.nih.gov/pubmed/37365519
http://dx.doi.org/10.1186/s10020-023-00667-w
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