The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation.
Genes Dev
; 34(17-18): 1177-1189, 2020 09 01.
Article
in En
| MEDLINE
| ID: mdl-32792353
ABSTRACT
Dysregulation of the ubiquitin-proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development. Using proteomic analysis of the Daam2-VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase Nedd4 is required for developmental myelination through stabilization of VHL via K63-linked ubiquitination. Furthermore, studies in mouse demyelination models and white matter lesions from patients with multiple sclerosis corroborate the function of this pathway during remyelination after WMI. Overall, these studies provide evidence that a signaling axis involving key UPS components contributes to oligodendrocyte development and repair and reveal a new role for Nedd4 in glial biology.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Differentiation
/
Oligodendroglia
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Rho GTP-Binding Proteins
/
Von Hippel-Lindau Tumor Suppressor Protein
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Nedd4 Ubiquitin Protein Ligases
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Microfilament Proteins
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Nerve Regeneration
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Nervous System Diseases
Limits:
Animals
/
Humans
Language:
En
Journal:
Genes Dev
Journal subject:
BIOLOGIA MOLECULAR
Year:
2020
Type:
Article
Affiliation country:
United States