Constitutively active Akt induces enhanced myelination in the CNS

Ana I. Flores, S. Priyadarshini Narayanan, Emily N. Morse, H. Elizabeth Shick, Xinghua Yin, Grahame Kidd, Robin L. Avila, Daniel A. Kirschner, Wendy B. Macklin

Research output: Contribution to journalArticle

225 Scopus citations

Abstract

The serine/threonine kinase Akt regulates multiple cellular functions. The current studies identify a new role for Akt in CNS myelination. In earlier studies on cultured oligodendrocytes, we showed that neuregulin signals through phosphatidylinositol-3′-OH kinase and Akt to enhance survival of oligodendrocytes. However, when transgenic animals were generated that overexpressed constitutively active Akt in oligodendrocytes and their progenitor cells, no enhanced survival of oligodendrocytes or progenitors was found. No alteration in the proliferation or death of progenitors was noted. In contrast, the major impact of Akt overexpression in oligodendrocytes was enhanced myelination. Most interestingly, oligodendrocytes in these mice continued actively myelinating throughout life. Thus, expression of constitutively active Akt in oligodendrocytes and their progenitor cells generated no more oligodendrocytes, but dramatically more myelin. The increased myelination continued as these mice aged, resulting in enlarged optic nerves and white matter areas. In older animals with enlarged white matter areas, the density of oligodendrocytes was reduced, but because of the increased area, the total number of oligodendrocytes remained comparable with wild-type controls. Interestingly, in these animals, overexpression of Akt in Schwann cells did not impact myelination. Thus, in vivo, constitutively active Akt enhances CNS myelination but not PNS myelination and has no impact developmentally on oligodendrocyte number. Understanding the unique aspects of Akt signal transduction in oligodendrocytes that lead to myelination rather than uncontrolled proliferation of oligodendrocyte progenitor cells may have important implications for understanding remyelination in the adult nervous system.

Original languageEnglish (US)
Pages (from-to)7174-7183
Number of pages10
JournalJournal of Neuroscience
Volume28
Issue number28
DOIs
StatePublished - Jul 9 2008

Keywords

  • Akt
  • Myelin
  • Oligodendrocyte
  • Phosphatidylinositol-3′-OH kinase
  • Schwann cell
  • Transgenic

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Flores, A. I., Narayanan, S. P., Morse, E. N., Shick, H. E., Yin, X., Kidd, G., Avila, R. L., Kirschner, D. A., & Macklin, W. B. (2008). Constitutively active Akt induces enhanced myelination in the CNS. Journal of Neuroscience, 28(28), 7174-7183. https://doi.org/10.1523/JNEUROSCI.0150-08.2008