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SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity

Author

Listed:
  • Li Liu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine
    Zhejiang University)

  • Zhigang Gao

    (National Clinical Research Center for Child Health)

  • Xueyuan Niu

    (Wenzhou Medical University)

  • Hong Yu

    (Zhejiang University School of Medicine)

  • Xiaolong Xin

    (Zhejiang University School of Medicine)

  • Yanlan Gu

    (Zhejiang University School of Medicine)

  • Genghai Ma

    (Qixia City People’s Hospital)

  • Yan Gu

    (Zhejiang University School of Medicine)

  • Yijun Liu

    (Zhejiang University School of Medicine)

  • Sanhua Fang

    (Zhejiang University School of Medicine)

  • Till Marquardt

    (RWTH Aachen University)

  • Liang Wang

    (Zhejiang University School of Medicine
    Zhejiang University)

Abstract

During peripheral nerve (PN) development, unmyelinated axons (nmAs) tightly fasciculate before being separated and enveloped by non-myelinating Schwann cells (nmSCs), glial cells essential for maintaining nmA integrity. How such a switch from axon-axon to axon-glia interactions is achieved remains poorly understood. Here, we find that inactivating SC-derived SEMA3B or its axonal receptor components in mice leads to incomplete nmA separation and envelopment by nmSCs, eliciting hyperalgesia and allodynia. Conversely, increasing SEMA3B levels in SCs accelerates nmA separation and envelopment. SEMA3B transiently promotes nmA defasciculation accompanied by cell adhesion molecule (CAM) endocytosis, subsequently facilitating nmA-nmSC association. Restoring SEMA3B expression following PN injury promotes nmA-nmSC re-association and alleviates hyperalgesia and allodynia. We propose that SEMA3B-induced CAM turnover facilitates a switch from axon-axon to axon-glia interactions promoting nmA envelopment by nmSCs, which may be exploitable for alleviating PN injury-induced pain by accelerating the restoration of nmA integrity.

Suggested Citation

  • Li Liu & Zhigang Gao & Xueyuan Niu & Hong Yu & Xiaolong Xin & Yanlan Gu & Genghai Ma & Yan Gu & Yijun Liu & Sanhua Fang & Till Marquardt & Liang Wang, 2025. "SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61318-8
    DOI: 10.1038/s41467-025-61318-8
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    References listed on IDEAS

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    1. Vijayan Gangadharan & Hongwei Zheng & Francisco J. Taberner & Jonathan Landry & Timo A. Nees & Jelena Pistolic & Nitin Agarwal & Deepitha Männich & Vladimir Benes & Moritz Helmstaedter & Björn Ommer &, 2022. "Neuropathic pain caused by miswiring and abnormal end organ targeting," Nature, Nature, vol. 606(7912), pages 137-145, June.
    2. Ruobo Zhou & Boran Han & Roberta Nowak & Yunzhe Lu & Evan Heller & Chenglong Xia & Athar H. Chishti & Velia M. Fowler & Xiaowei Zhuang, 2022. "Proteomic and functional analyses of the periodic membrane skeleton in neurons," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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