Building White Matter: The Role of PI(3,5)P2 Biosynthesis in Myelin formation, Stability, and Repair.

[摘要] Neuron-glia interactions are the cornerstone of a functional nervous system. Formation of white matter (myelin) is mediated by neurons and myelinating glia and is essential for the rapid propagation of action potentials. Increased white matter volume is evolutionarily correlated with cognitive superiority of higher vertebrates. Impaired myelin formation or damage to the existing myelin sheath have devastating functional consequences, such as paralysis, intellectual disability, and blindness. In the central nervous system (CNS), myelin formation and maintenance are highly orchestrated multi-step processes that require proper migration, neuronal contact, and differentiation of oligodendrocyte precursors (OPCs), mediated by both intrinsic and extrinsic mechanisms. Here we demonstrate that one of the most fundamental eukaryotic cell processes – intracellular trafficking – plays a crucial role in CNS myelination. In particular, we show that the signaling lipid phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] is required in neurons and in oligodendrocytes (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 or Pikfyve accumulate large vesicular structures and exhibit impaired terminal differentiation. Live-cell imaging of OLs after genetic or pharmacological inhibition of PI(3,5)P2 synthesis reveals impaired trafficking of myelin building blocks through the endolysosomal system in primary cells and brain tissue. To test whether PI(3,5)P2 biosynthesis is required for adult myelin maintenance and repair, we generatedtamoxifen-inducible global Fig4 knockout mice, Fig4-/flox,CAGCreER.Strikingly, adult Fig4 deletion leads to rapid deterioration in mice with severe motor impairment, tremor, weight loss, and death within two months of Cre induction. The peripheral nervous system (PNS) shows severe defects, suggestive of damaged neurons and Schwann cells, the PNS myelinating glia. In the same animals, CNS myelin remains relatively intact, demonstrating differential vulnerability of myelinated CNS vs. PNS fibers to impaired PI(3,5)P2 biosynthesis.Our preliminary data suggest that inducible Fig4 loss in adult mice prevents CNS myelin repair. Collectively, my thesis work extends understanding of the PI(3,5)P2 biosynthetic complex as a key regulator of CNS and PNS myelin formation and dynamics.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Intracellular trafficking in myelination;Molecular;Cellular and Developmental Biology;Health Sciences;Cellular and Molecular Biology