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 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.

Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter

“…While the molecular machinery regulating surface trafficking of metabolite transporters in OLs is still poorly understood, studies on adipocytes showed that VAMP2 and RAB5 family of GTPases are involved in GLUT4 glucose transporter trafficking [87][88][89] . Of note, VAMP2/3mediated exocytosis promotes membrane expansion in OLs and myelin formation during development 90 and VAMP3 regulates surface transport of the myelin protein PLP 91,92 . In Kir4.1 cKO mice, myelin sheath thickness and abundance of PLP in myelin was not affected, which is not surprising given that other transport-regulating proteins such as VAMP7 are also involved in PLP trafficking 91,92 .…”