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.
Highlights
In the vertebrate CNS, the majority of long axons are myelinated
Our study shows that multiple strategies to perturb the FIG4/PIKFYVE/VAC14 enzyme complex, and by extension the lipid product PI(3,5)P2, result in the common endpoints of arrested OL differentiation, impaired myelin protein trafficking through the late endosomal/ lysosomal (LE/Lys) compartment, and severe CNS hypomyelination
For a quantitative comparison of the myelination defects, whole brain membranes were prepared from P21 pups and analyzed by immunoblotting with antibodies specific for the myelin markers myelin-associated glycoprotein (MAG), 2’,3’-cyclic-nucleotide 3’-phosphodiesterase (CNPase), proteolipid protein (PLP), and myelin basic protein (MBP) (Figure 1E)
Summary
In the vertebrate CNS, the majority of long axons are myelinated. Myelin greatly increases the conduction velocity of action potentials and provides metabolic support for axons. Bidirectional axo-glial signaling is critical for nervous system myelination and fiber stability (Nave and Trapp, 2008; Simons and Lyons, 2013). Myelin development is regulated by oligodendrocyte (OL) intrinsic mechanisms (Zuchero and Barres, 2013), astrocyte secreted factors (Ishibashi et al, 2006), neuronal electrical activity (Barres and Raff, 1993; Ishibashi et al, 2006) and axon derived chemical signals (Coman et al, 2005; Ohno et al, 2009; Winters et al, 2011, Yao et al, 2014)
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