Opposing extracellular signal-regulated kinase and Akt pathways control schwann cell myelination

Toru Ogata, Satoru Iijima, Shinya Hoshikawa, Toshiki Miura, Shin Ichi Yamamoto, Hiromi Oda, Kozo Nakamura, Sakae Tanaka

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Schwann cells are the myelinating glia of the peripheral nervous system, and their development is regulated by various growth factors, such as neuregulin, platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). However, the mechanism of intracellular signaling pathways following these ligand stimuli in Schwann cell differentiation remains elusive. Here, we demonstrate that in cultured Schwann cells, neuregulin and PDGF suppressed the expression of myelin-associated protein markers, whereas IGF-I promoted it. Although these ligands activated common downstream signaling pathways [i.e., extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways], the profiles of activation varied among ligands. To elucidate the function of these pathways and the mechanisms underlying Schwann cell differentiation, we used adenoviral vectors to selectively activate or inactivate these pathways. We found that the selective activation of Erk pathways suppressed Schwann cell differentiation, whereas that of PI3K pathways promoted it. Furthermore, lithium chloride, a modulator of glycogen synthase kinase-3β (GSK-3β) promoted Schwann cell differentiation, suggesting the involvement of GSK-3β as a downstream molecule of PI3K-Akt pathways. Selective activation of PI3K pathways in Schwann cells by gene transfer also demonstrated increased myelination in in vitro Schwann cell-DRG neuron cocultures and in vivo allogenic nerve graft experiments. We conclude that signals mediated by PI3K-Akt are crucial for initiation of myelination and that the effects of growth factors are primarily dependent on the balance between Erk and PI3K-Akt activation. Our results also propose the possibility of augmenting Schwann cell functions by modulating intracellular signals in light of future cell therapies.

Original languageEnglish
Pages (from-to)6724-6732
Number of pages9
JournalJournal of Neuroscience
Volume24
Issue number30
DOIs
Publication statusPublished - 2004 Jul 28

Keywords

  • Glia
  • Intracellular
  • Myelin
  • Peripheral nerve
  • Regeneration
  • Transplantation

ASJC Scopus subject areas

  • Neuroscience(all)

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