title: PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms.
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.
authors.affiliation: Department 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 States.
authors.forename: Yevgeniya A
authors.initials: YA
authors.lastname: Mironova
authors.affiliation: Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, United States.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Lin
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, United States.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, United States.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Twiss
authors.affiliation: Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Vaccari
authors.affiliation: Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, United States.
authors.forename: Leif A
authors.initials: LA
authors.lastname: Havton
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States.
authors.forename: Sang H
authors.initials: SH
authors.lastname: Min
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Abrams
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Shrager
authors.affiliation: Department 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 States.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.affiliation: Department 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 States.
authors.forename: Roman J
authors.identifier: 0000-0002-2926-3336
authors.initials: RJ
authors.lastname: Giger
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D017353:Gene Deletion; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects* / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis*
chemical_list: D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate
keywords: axo-glial interaction; lysosome; membrane transport; mouse; neuroscience; oligodendrocytes; optic nerve