PIKE is essential for oligodendroglia development and CNS myelination

Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1993-8. doi: 10.1073/pnas.1318185111. Epub 2014 Jan 21.

Abstract

Oligodendrocyte (OL) differentiation and myelin development are complex events regulated by numerous signal transduction factors. Here, we report that phosphoinositide-3 kinase enhancer L (PIKE-L) is required for OL development and myelination. PIKE-L expression is up-regulated when oligodendrocyte progenitor cells commit to differentiation. Conversely, depleting phosphoinositide-3 kinase enhancer (PIKE) expression by shRNA prevents oligodendrocyte progenitor cell differentiation. In both conventional PIKE knockout (PIKE(-/-)) and OL-specific PIKE knockout mice, the number of OLs is reduced in the corpus callosum. PIKE(-/-) OLs also display defects when forming myelin sheath on neuronal axons during neonatal development, which is partially rescued when PTEN is ablated. In addition, Akt/mTOR signaling is impaired in OL-enriched tissues of the PIKE(-/-) mutant, leading to reduced expression of critical proteins for myelin development and hypomyelination. Moreover, myelin repair of lysolecithin-induced lesions is delayed in PIKE(-/-) brain. Thus, PIKE plays pivotal roles to advance OL development and myelinogenesis through Akt/mTOR activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / metabolism
  • Brain / growth & development
  • Brain / pathology
  • Brain / ultrastructure
  • Cell Count
  • Cells, Cultured
  • Central Nervous System / growth & development
  • Central Nervous System / metabolism*
  • GTP Phosphohydrolases / metabolism*
  • Mice
  • Mice, Knockout
  • Monomeric GTP-Binding Proteins / metabolism*
  • Mutation / genetics
  • Myelin Sheath / metabolism
  • Myelin Sheath / ultrastructure
  • Nerve Tissue Proteins / metabolism*
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Oligodendroglia / ultrastructure
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Up-Regulation

Substances

  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Agap2 protein, rat
  • GTP Phosphohydrolases
  • PIKE protein, mouse
  • Monomeric GTP-Binding Proteins