PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms
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
Affiliations
Yevgeniya A Mironova
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
Guy M Lenk
Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, United States
Jing-Ping Lin
Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, United States
Seung Joon Lee
Department of Biological Sciences, University of South Carolina, Columbia, United States
Jeffery L Twiss
Department of Biological Sciences, University of South Carolina, Columbia, United States
Ilaria Vaccari
Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
Alessandra Bolino
Human Inherited Neuropathies Unit, INSPE-Institute for Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
Leif A Havton
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, United States
Sang H Min
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States
Charles S Abrams
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, United States
Peter Shrager
Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, United States
Miriam H Meisler
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
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
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.
