PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms
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, Pi...
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doaj-d7e8943d1aa8488ab6ee92800452d7542021-05-05T00:19:42ZengeLife Sciences Publications LtdeLife2050-084X2016-03-01510.7554/eLife.13023PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanismsYevgeniya A Mironova0Guy M Lenk1Jing-Ping Lin2Seung Joon Lee3Jeffery L Twiss4Ilaria Vaccari5Alessandra Bolino6Leif A Havton7Sang H Min8Charles S Abrams9Peter Shrager10Miriam H Meisler11Roman J Giger12https://orcid.org/0000-0002-2926-3336Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States; Cellular and Molecular Biology Graduate Program, University of Michigan School of Medicine, Ann Arbor, United StatesDepartment of Human Genetics, University of Michigan School of Medicine, Ann Arbor, United StatesDepartment of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United StatesDepartment of Biological Sciences, University of South Carolina, Columbia, United StatesDepartment of Biological Sciences, University of South Carolina, Columbia, United StatesHuman Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, ItalyHuman Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, ItalyDepartment of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, United StatesDepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United StatesDepartment of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United StatesDepartment of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, United StatesDepartment of Human Genetics, University of Michigan School of Medicine, Ann Arbor, United States; Department of Neurology, University of Michigan School of Medicine, Ann Arbor, United StatesDepartment of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States; Department of Neurology, University of Michigan School of Medicine, Ann Arbor, United StatesProper 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.https://elifesciences.org/articles/13023oligodendrocytesoptic nerveaxo-glial interactionmembrane transportlysosome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yevgeniya A Mironova Guy M Lenk Jing-Ping Lin Seung Joon Lee Jeffery L Twiss Ilaria Vaccari Alessandra Bolino Leif A Havton Sang H Min Charles S Abrams Peter Shrager Miriam H Meisler Roman J Giger |
spellingShingle |
Yevgeniya A Mironova Guy M Lenk Jing-Ping Lin Seung Joon Lee Jeffery L Twiss Ilaria Vaccari Alessandra Bolino Leif A Havton Sang H Min Charles S Abrams Peter Shrager Miriam H Meisler Roman J Giger PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms eLife oligodendrocytes optic nerve axo-glial interaction membrane transport lysosome |
author_facet |
Yevgeniya A Mironova Guy M Lenk Jing-Ping Lin Seung Joon Lee Jeffery L Twiss Ilaria Vaccari Alessandra Bolino Leif A Havton Sang H Min Charles S Abrams Peter Shrager Miriam H Meisler Roman J Giger |
author_sort |
Yevgeniya A Mironova |
title |
PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_short |
PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_full |
PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_fullStr |
PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_full_unstemmed |
PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
title_sort |
pi(3,5)p2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2016-03-01 |
description |
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. |
topic |
oligodendrocytes optic nerve axo-glial interaction membrane transport lysosome |
url |
https://elifesciences.org/articles/13023 |
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