PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms

  1. Yevgeniya A Mironova
  2. Guy M Lenk
  3. Jing-Ping Lin
  4. Seung Joon Lee
  5. Jeffery L Twiss
  6. Ilaria Vaccari
  7. Alessandra Bolino
  8. Leif A Havton
  9. Sang H Min
  10. Charles S Abrams
  11. Peter Shrager
  12. Miriam H Meisler
  13. Roman J Giger  Is a corresponding author
  1. University of Michigan School of Medicine, United States
  2. University of South Carolina, United States
  3. San Raffaele Scientific Institute, Italy
  4. David Geffen School of Medicine at UCLA, United States
  5. University of Pennsylvania School of Medicine, United States
  6. University of Rochester Medical Center, United States

Abstract

Proper development of the CNS axon-glia unit requires bi-directional communication between axons and oligodendrocytes (OLs). We show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] is required in neurons and in OLs for normal CNS myelination. In mice, mutations of Fig4, Pikfyve or Vac14, encoding key components of the PI(3,5)P2 biosynthetic complex, each lead to impaired OL maturation, severe CNS hypomyelination and delayed propagation of compound action potentials. Primary OLs deficient in Fig4 accumulate large LAMP1+ and Rab7+ vesicular structures and exhibit reduced membrane sheet expansion. PI(3,5)P2 deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMP1+ perinuclear vesicles that fail to migrate to the nascent myelin sheet. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P2 synthesis revealed impaired trafficking of plasma membrane-derived MAG through the endolysosomal system in primary cells and brain tissue. Collectively, our studies identify PI(3,5)P2 as a key regulator of myelin membrane trafficking and myelinogenesis.

Article and author information

Author details

  1. Yevgeniya A Mironova

    Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Guy M Lenk

    Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jing-Ping Lin

    Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Seung Joon Lee

    Department of Biological Sciences, University of South Carolina, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeffery L Twiss

    Department of Biological Sciences, University of South Carolina, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ilaria Vaccari

    Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Alessandra Bolino

    Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Leif A Havton

    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sang H Min

    Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Charles S Abrams

    Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter Shrager

    Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Miriam H Meisler

    Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Roman J Giger

    Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States
    For correspondence
    rgiger@med.umich.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Ben Barres, Stanford School of Medicine, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to protocols approved by the University committee on use and care for animals (UCUCA protocols: #00005863 and #00005902) of the University of Michigan.

Version history

  1. Received: November 13, 2015
  2. Accepted: March 23, 2016
  3. Accepted Manuscript published: March 23, 2016 (version 1)
  4. Version of Record published: June 1, 2016 (version 2)

Copyright

© 2016, Mironova et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yevgeniya A Mironova
  2. Guy M Lenk
  3. Jing-Ping Lin
  4. Seung Joon Lee
  5. Jeffery L Twiss
  6. Ilaria Vaccari
  7. Alessandra Bolino
  8. Leif A Havton
  9. Sang H Min
  10. Charles S Abrams
  11. Peter Shrager
  12. Miriam H Meisler
  13. Roman J Giger
(2016)
PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms
eLife 5:e13023.
https://doi.org/10.7554/eLife.13023

Share this article

https://doi.org/10.7554/eLife.13023

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