SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity
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...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61318-8 |
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| author | Li Liu Zhigang Gao Xueyuan Niu Hong Yu Xiaolong Xin Yanlan Gu Genghai Ma Yan Gu Yijun Liu Sanhua Fang Till Marquardt Liang Wang |
| author_facet | Li Liu Zhigang Gao Xueyuan Niu Hong Yu Xiaolong Xin Yanlan Gu Genghai Ma Yan Gu Yijun Liu Sanhua Fang Till Marquardt Liang Wang |
| author_sort | Li Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-903731c8f85a425c94357e7f1114b51e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-903731c8f85a425c94357e7f1114b51e2025-08-20T04:01:35ZengNature PortfolioNature Communications2041-17232025-07-0116111910.1038/s41467-025-61318-8SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrityLi Liu0Zhigang Gao1Xueyuan Niu2Hong Yu3Xiaolong Xin4Yanlan Gu5Genghai Ma6Yan Gu7Yijun Liu8Sanhua Fang9Till Marquardt10Liang Wang11Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of MedicineDepartment of Pediatric General Surgery, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHistology and Embryology Teaching and Research Section, School of Basic Medical Sciences, Wenzhou Medical UniversityDepartment of General Surgery of Sir Run Run Shaw Hospital, Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Zhejiang University School of MedicineDepartment of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of MedicineDepartment of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of MedicineDepartment of Extra Osseous, Qixia City People’s HospitalCenter of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of MedicineCore Facilities, Zhejiang University School of MedicineInterfaculty Chair for Neurobiological Research, Clinic for Neurology, RWTH Aachen University Medical Faculty (UKA) & Institute for Biology 2, Faculty for Mathematics, Computer and Natural Sciences, RWTH Aachen UniversityDepartment of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-61318-8 |
| spellingShingle | Li Liu Zhigang Gao Xueyuan Niu Hong Yu Xiaolong Xin Yanlan Gu Genghai Ma Yan Gu Yijun Liu Sanhua Fang Till Marquardt Liang Wang SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity Nature Communications |
| title | SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity |
| title_full | SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity |
| title_fullStr | SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity |
| title_full_unstemmed | SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity |
| title_short | SEMA3B switches axon-axon to axon-glia interactions required for unmyelinated axon envelopment and integrity |
| title_sort | sema3b switches axon axon to axon glia interactions required for unmyelinated axon envelopment and integrity |
| url | https://doi.org/10.1038/s41467-025-61318-8 |
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