FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system
Abstract Myelin, along with the oligodendrocytes (OLs) that produce it, is essential for proper central nervous system (CNS) function in vertebrates. Although the accurate targeting of myelin to axons and its maintenance are critical for CNS performance, the molecular pathways that regulate these pr...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62715-9 |
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| author | Hannah Y. Collins Ryan A. Doan Jiaxing Li Jason E. Early Megan E. Madden Tyrell Simkins David A. Lyons Kelly R. Monk Ben Emery |
| author_facet | Hannah Y. Collins Ryan A. Doan Jiaxing Li Jason E. Early Megan E. Madden Tyrell Simkins David A. Lyons Kelly R. Monk Ben Emery |
| author_sort | Hannah Y. Collins |
| collection | DOAJ |
| description | Abstract Myelin, along with the oligodendrocytes (OLs) that produce it, is essential for proper central nervous system (CNS) function in vertebrates. Although the accurate targeting of myelin to axons and its maintenance are critical for CNS performance, the molecular pathways that regulate these processes remain poorly understood. Through a combination of zebrafish genetics, mouse models, and primary OL cultures, we find that FBXW7, a recognition subunit of an E3 ubiquitin ligase complex, is a regulator of adult myelination in the CNS. Loss of Fbxw7 in myelinating OLs results in increased myelin sheath lengths with no change in myelin thickness. As the animals age, they develop progressive abnormalities including myelin outfolds, disrupted paranodal organization, and ectopic ensheathment of neuronal cell bodies with myelin. Through biochemical studies we find that FBXW7 directly binds and degrades the N-terminus of Myelin Regulatory Factor (N-MYRF), to control the balance between OL myelin growth and homeostasis. |
| format | Article |
| id | doaj-art-28205be2d08244ad98d7aead0bc8e788 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-28205be2d08244ad98d7aead0bc8e7882025-08-24T11:36:42ZengNature PortfolioNature Communications2041-17232025-08-0116111910.1038/s41467-025-62715-9FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous systemHannah Y. Collins0Ryan A. Doan1Jiaxing Li2Jason E. Early3Megan E. Madden4Tyrell Simkins5David A. Lyons6Kelly R. Monk7Ben Emery8Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science UniversityVollum Institute, Oregon Health & Science UniversityVollum Institute, Oregon Health & Science UniversityCentre for Discovery Brain Sciences, MS Society Edinburgh Centre for MS Research, University of EdinburghCentre for Discovery Brain Sciences, MS Society Edinburgh Centre for MS Research, University of EdinburghJungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science UniversityCentre for Discovery Brain Sciences, MS Society Edinburgh Centre for MS Research, University of EdinburghVollum Institute, Oregon Health & Science UniversityJungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science UniversityAbstract Myelin, along with the oligodendrocytes (OLs) that produce it, is essential for proper central nervous system (CNS) function in vertebrates. Although the accurate targeting of myelin to axons and its maintenance are critical for CNS performance, the molecular pathways that regulate these processes remain poorly understood. Through a combination of zebrafish genetics, mouse models, and primary OL cultures, we find that FBXW7, a recognition subunit of an E3 ubiquitin ligase complex, is a regulator of adult myelination in the CNS. Loss of Fbxw7 in myelinating OLs results in increased myelin sheath lengths with no change in myelin thickness. As the animals age, they develop progressive abnormalities including myelin outfolds, disrupted paranodal organization, and ectopic ensheathment of neuronal cell bodies with myelin. Through biochemical studies we find that FBXW7 directly binds and degrades the N-terminus of Myelin Regulatory Factor (N-MYRF), to control the balance between OL myelin growth and homeostasis.https://doi.org/10.1038/s41467-025-62715-9 |
| spellingShingle | Hannah Y. Collins Ryan A. Doan Jiaxing Li Jason E. Early Megan E. Madden Tyrell Simkins David A. Lyons Kelly R. Monk Ben Emery FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system Nature Communications |
| title | FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system |
| title_full | FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system |
| title_fullStr | FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system |
| title_full_unstemmed | FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system |
| title_short | FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult central nervous system |
| title_sort | fbxw7 regulates myrf levels to control myelin capacity and homeostasis in the adult central nervous system |
| url | https://doi.org/10.1038/s41467-025-62715-9 |
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