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bioRxiv · 10.1101/2022.07.08.498895

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

Lam, M.·Takeo, K.·Almeida, R. G.·Cooper, M. H.·Wu, K.·Iyer, M.·Kantarci, H.·Zuchero, J. B.
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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 unknown. 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.

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Lam, M., Takeo, K., Almeida, R. G., Cooper, M. H., Wu, K., Iyer, M., Kantarci, H., Zuchero, J. B.. 2022-07-10. CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes. https://doi.org/10.1101/2022.07.08.498895

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