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

• DOI: 10.1101/2022.07.08.498895
• Publication Date: 2022-07-10T23:15:16Z
• Authors: Mable Lam; Koji Takeo; Rafael G. Almeida; Madeline H. Cooper; Kathryn Wu; Manasi Iyer; Husniye Kantarci; J. Bradley Zuchero
• Keywords: 0301 basic medicine; 0303 health sciences; Vesicle-Associated Membrane Protein 2; Science; Q; Article; Axons; 3. Good health; Oligodendroglia; 03 medical and health sciences; Myelin Proteins; Myelin Sheath

AbstractMyelin 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.