OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation.
Proc Natl Acad Sci U S A
; 121(32): e2403652121, 2024 Aug 06.
Article
em En
| MEDLINE
| ID: mdl-39083419
ABSTRACT
Leucine-rich glioma-inactivated protein 1 (LGI1), a secretory protein in the brain, plays a critical role in myelination; dysfunction of this protein leads to hypomyelination and white matter abnormalities (WMAs). Here, we hypothesized that LGI1 may regulate myelination through binding to an unidentified receptor on the membrane of oligodendrocytes (OLs). To search for this hypothetic receptor, we analyzed LGI1 binding proteins through LGI1-3 × FLAG affinity chromatography with mouse brain lysates followed by mass spectrometry. An OL-specific membrane protein, the oligodendrocytic myelin paranodal and inner loop protein (OPALIN), was identified. Conditional knockout (cKO) of OPALIN in the OL lineage caused hypomyelination and WMAs, phenocopying LGI1 deficiency in mice. Biochemical analysis revealed the downregulation of Sox10 and Olig2, transcription factors critical for OL differentiation, further confirming the impaired OL maturation in Opalin cKO mice. Moreover, virus-mediated re-expression of OPALIN successfully restored myelination in Opalin cKO mice. In contrast, re-expression of LGI1-unbound OPALIN_K23A/D26A failed to reverse the hypomyelination phenotype. In conclusion, our study demonstrated that OPALIN on the OL membrane serves as an LGI1 receptor, highlighting the importance of the LGI1/OPALIN complex in orchestrating OL differentiation and myelination.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Oligodendroglia
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Camundongos Knockout
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Peptídeos e Proteínas de Sinalização Intracelular
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
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Proc. Natl. Acad. Sci. U. S. A
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Proceedings of the national academy of sciences of the United States of America
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China