Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination

Highlights

• Schwann cell (SC)-specific inactivation of PI4KA causes myelination defects in mice

• Inhibition of PI4KA did not decrease PI(4,5)P₂ levels or PI(3,4,5)P₃ responses in SCs

• SC-specific PI4KA inactivation caused major decreases in PS, PE, and sphingomyelin

• PI4KA inactivation caused actin disorganization in sciatic nerves and SCs

Summary

Active membrane remodeling during myelination relies on phospholipid synthesis and membrane polarization, both of which are known to depend on inositol phospholipids. Here, we show that sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions. Surprisingly, prolonged inhibition of PI4KA in immortalized mouse SCs failed to decrease plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) levels or PI 3-kinase (PI3K) activation, in spite of large reductions in plasma membrane PI4P levels. Instead, it caused rearrangements of the actin cytoskeleton, which was also observed in sciatic nerves of knockout animals. PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor. These studies define a role for PI4KA in myelin formation primarily affecting metabolism of key phospholipids and the actin cytoskeleton.