GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand
Abstract The neurotrophic factor, Glial cell line derived neurotrophi factor (GDNF), exerts a variety of biological effects through binding to its receptors, GDNF family receptor alpha‐1 (GFRα1), and RET. However, the existence of cells expressing GFRα1 but not RET raises the possibility that GFRα1...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202400812 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582739872710656 |
|---|---|
| author | Tomoaki Suzuki Ken Kadoya Takeshi Endo Miwako Yamasaki Masahiko Watanabe Norimasa Iwasaki |
| author_facet | Tomoaki Suzuki Ken Kadoya Takeshi Endo Miwako Yamasaki Masahiko Watanabe Norimasa Iwasaki |
| author_sort | Tomoaki Suzuki |
| collection | DOAJ |
| description | Abstract The neurotrophic factor, Glial cell line derived neurotrophi factor (GDNF), exerts a variety of biological effects through binding to its receptors, GDNF family receptor alpha‐1 (GFRα1), and RET. However, the existence of cells expressing GFRα1 but not RET raises the possibility that GFRα1 can function independently from RET. Here, it is shown that GFRα1 released from repair Schwann cells (RSCs) functions as a ligand in a GDNF‐RET‐independent manner to promote axon regeneration after peripheral nerve injury (PNI). Local administration of GFRα1 into injured nerve promoted axon regeneration, even more when combined with GDNF blockade. GFRα1 bound to a receptor complex consisting of NCAM and integrin α7β1 of dorsal root ganglion neurons in a GDNF‐RET independent manner. This is further confirmed by the Ret Y1062F knock‐in mice, which cannot transmit most of GDNF‐RET signaling. Finally, local administration of GFRα1 into injured sciatic nerve promoted functional recovery. These findings reveal a novel role of GFRα1 as a ligand, the molecular mechanism supporting axon regeneration by RSCs, and a novel therapy for peripheral nerve repair. |
| format | Article |
| id | doaj-art-3881bbd373a649eead17ab06fc5de3c1 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-3881bbd373a649eead17ab06fc5de3c12025-01-29T09:50:18ZengWileyAdvanced Science2198-38442025-01-01124n/an/a10.1002/advs.202400812GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a LigandTomoaki Suzuki0Ken Kadoya1Takeshi Endo2Miwako Yamasaki3Masahiko Watanabe4Norimasa Iwasaki5Department of Orthopaedic Surgery Graduate School of Medicine Hokkaido University Sapporo Hokkaido 0608638 JapanDepartment of Orthopaedic Surgery Graduate School of Medicine Hokkaido University Sapporo Hokkaido 0608638 JapanDepartment of Orthopaedic Surgery Graduate School of Medicine Hokkaido University Sapporo Hokkaido 0608638 JapanDepartment of Anatomy Graduate School of Medicine, Hokkaido University Sapporo Hokkaido 0608638 JapanDepartment of Anatomy Graduate School of Medicine, Hokkaido University Sapporo Hokkaido 0608638 JapanDepartment of Orthopaedic Surgery Graduate School of Medicine Hokkaido University Sapporo Hokkaido 0608638 JapanAbstract The neurotrophic factor, Glial cell line derived neurotrophi factor (GDNF), exerts a variety of biological effects through binding to its receptors, GDNF family receptor alpha‐1 (GFRα1), and RET. However, the existence of cells expressing GFRα1 but not RET raises the possibility that GFRα1 can function independently from RET. Here, it is shown that GFRα1 released from repair Schwann cells (RSCs) functions as a ligand in a GDNF‐RET‐independent manner to promote axon regeneration after peripheral nerve injury (PNI). Local administration of GFRα1 into injured nerve promoted axon regeneration, even more when combined with GDNF blockade. GFRα1 bound to a receptor complex consisting of NCAM and integrin α7β1 of dorsal root ganglion neurons in a GDNF‐RET independent manner. This is further confirmed by the Ret Y1062F knock‐in mice, which cannot transmit most of GDNF‐RET signaling. Finally, local administration of GFRα1 into injured sciatic nerve promoted functional recovery. These findings reveal a novel role of GFRα1 as a ligand, the molecular mechanism supporting axon regeneration by RSCs, and a novel therapy for peripheral nerve repair.https://doi.org/10.1002/advs.202400812axon regenerationGDNF family receptorperipheral nerve injuryrepair schwann cells |
| spellingShingle | Tomoaki Suzuki Ken Kadoya Takeshi Endo Miwako Yamasaki Masahiko Watanabe Norimasa Iwasaki GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand Advanced Science axon regeneration GDNF family receptor peripheral nerve injury repair schwann cells |
| title | GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand |
| title_full | GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand |
| title_fullStr | GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand |
| title_full_unstemmed | GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand |
| title_short | GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand |
| title_sort | gfrα1 promotes axon regeneration after peripheral nerve injury by functioning as a ligand |
| topic | axon regeneration GDNF family receptor peripheral nerve injury repair schwann cells |
| url | https://doi.org/10.1002/advs.202400812 |
| work_keys_str_mv | AT tomoakisuzuki gfra1promotesaxonregenerationafterperipheralnerveinjurybyfunctioningasaligand AT kenkadoya gfra1promotesaxonregenerationafterperipheralnerveinjurybyfunctioningasaligand AT takeshiendo gfra1promotesaxonregenerationafterperipheralnerveinjurybyfunctioningasaligand AT miwakoyamasaki gfra1promotesaxonregenerationafterperipheralnerveinjurybyfunctioningasaligand AT masahikowatanabe gfra1promotesaxonregenerationafterperipheralnerveinjurybyfunctioningasaligand AT norimasaiwasaki gfra1promotesaxonregenerationafterperipheralnerveinjurybyfunctioningasaligand |