CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes
- PMID: 36151203
- PMCID: PMC9508103
- DOI: 10.1038/s41467-022-33200-4
CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes
Abstract
Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.
© 2022. The Author(s).
Conflict of interest statement
K.T. is an employee of Toray Industries, Inc. The remaining authors declare no competing interests.
Figures
![Fig. 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig1_HTML.gif)
![Fig. 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig2_HTML.gif)
![Fig. 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig3_HTML.gif)
![Fig. 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig4_HTML.gif)
![Fig. 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig5_HTML.gif)
![Fig. 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig6_HTML.gif)
![Fig. 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9508103/bin/41467_2022_33200_Fig7_HTML.gif)
Similar articles
-
Cleavage of VAMP2/3 Affects Oligodendrocyte Lineage Development in the Developing Mouse Spinal Cord.J Neurosci. 2023 Sep 27;43(39):6592-6608. doi: 10.1523/JNEUROSCI.2206-21.2023. Epub 2023 Aug 24. J Neurosci. 2023. PMID: 37620160 Free PMC article.
-
N-Wasp Regulates Oligodendrocyte Myelination.J Neurosci. 2020 Aug 5;40(32):6103-6111. doi: 10.1523/JNEUROSCI.0912-20.2020. Epub 2020 Jun 29. J Neurosci. 2020. PMID: 32601246 Free PMC article.
-
Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.J Neurosci. 2021 Sep 22;41(38):7954-7964. doi: 10.1523/JNEUROSCI.2463-20.2021. Epub 2021 Aug 2. J Neurosci. 2021. PMID: 34341156 Free PMC article.
-
[Oligodendrocytes have a key role in the development of CNS function and in myelin related diseases].Lakartidningen. 2000 Jul 12;97(28-29):3265-8. Lakartidningen. 2000. PMID: 10997013 Review. Swedish.
-
The cell biology of CNS myelination.Curr Opin Neurobiol. 2016 Aug;39:93-100. doi: 10.1016/j.conb.2016.04.013. Epub 2016 May 3. Curr Opin Neurobiol. 2016. PMID: 27152449 Free PMC article. Review.
Cited by
-
Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer's disease model mice.Nat Neurosci. 2024 Aug 5. doi: 10.1038/s41593-024-01730-3. Online ahead of print. Nat Neurosci. 2024. PMID: 39103558
-
Translating Molecular Approaches to Oligodendrocyte-Mediated Neurological Circuit Modulation.Brain Sci. 2024 Jun 27;14(7):648. doi: 10.3390/brainsci14070648. Brain Sci. 2024. PMID: 39061389 Free PMC article. Review.
-
Vesicle Fusion in Oligodendrocyte Maturation and Myelination.J Neurosci. 2024 Apr 17;44(16):e2203232024. doi: 10.1523/JNEUROSCI.2203-23.2024. J Neurosci. 2024. PMID: 38631918 No abstract available.
-
MicroRNAs dysregulated in multiple sclerosis affect the differentiation of CG-4 cells, an oligodendrocyte progenitor cell line.Front Cell Neurosci. 2024 Feb 29;18:1336439. doi: 10.3389/fncel.2024.1336439. eCollection 2024. Front Cell Neurosci. 2024. PMID: 38486710 Free PMC article.
-
Oligodendrocyte-axon metabolic coupling is mediated by extracellular K+ and maintains axonal health.Nat Neurosci. 2024 Mar;27(3):433-448. doi: 10.1038/s41593-023-01558-3. Epub 2024 Jan 24. Nat Neurosci. 2024. PMID: 38267524 Free PMC article.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials