PI(3,5)P-2 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 [P1(3,5)P-2] 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)P-2 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)P-2 deficiency leads to accumulation of myelin-associated glycoprotein (MAG) in LAMPl 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)P-2 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)P-2 as a key regulator of myelin membrane trafficking and myelinogenesis.