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

Cell Rep. 2018 Jun 5;23(10):2881-2890. doi: 10.1016/j.celrep.2018.05.019.


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.

Keywords: PI 3-kinase; Schwann cell; actin; myelination; phosphatidylinositol; phosphatidylinositol 4-kinase; phosphatidylserine; sciatic nerve.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Movement
  • Enzyme Activation
  • Gene Deletion*
  • Mice, Knockout
  • Minor Histocompatibility Antigens / metabolism*
  • Mutation / genetics
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Schwann Cells / enzymology*
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure
  • Sphingolipids / metabolism
  • TOR Serine-Threonine Kinases / metabolism


  • Actins
  • Minor Histocompatibility Antigens
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositol Phosphates
  • Sphingolipids
  • phosphatidylinositol 4-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases