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

Author

Listed:
  • Mable Lam

    (Stanford University School of Medicine)

  • Koji Takeo

    (Stanford University School of Medicine
    Pharmaceutical Research Laboratories, Toray Industries, Inc.)

  • Rafael G. Almeida

    (University of Edinburgh)

  • Madeline H. Cooper

    (Stanford University School of Medicine)

  • Kathryn Wu

    (Stanford University School of Medicine)

  • Manasi Iyer

    (Stanford University School of Medicine)

  • Husniye Kantarci

    (Stanford University School of Medicine)

  • J. Bradley Zuchero

    (Stanford University School of Medicine)

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.

Suggested Citation

  • Mable Lam & Koji Takeo & Rafael G. Almeida & Madeline H. Cooper & Kathryn Wu & Manasi Iyer & Husniye Kantarci & J. Bradley Zuchero, 2022. "CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33200-4
    DOI: 10.1038/s41467-022-33200-4
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    Cited by:

    1. Jianping Wu & Georg Kislinger & Jerome Duschek & Ayşe Damla Durmaz & Benedikt Wefers & Ruoqing Feng & Karsten Nalbach & Wolfgang Wurst & Christian Behrends & Martina Schifferer & Mikael Simons, 2024. "Nonvesicular lipid transfer drives myelin growth in the central nervous system," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Manasi Iyer & Husniye Kantarci & Madeline H. Cooper & Nicholas Ambiel & Sammy Weiser Novak & Leonardo R. Andrade & Mable Lam & Graham Jones & Alexandra E. Münch & Xinzhu Yu & Baljit S. Khakh & Uri Man, 2024. "Oligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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