Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways

Neuroscience. 2015 Jan 22;284:962-971. doi: 10.1016/j.neuroscience.2014.10.064. Epub 2014 Nov 5.

Abstract

Deciphering the molecular pathways involved in myelin gene expression is a major point of interest to better understand re/myelination processes. In this study, we investigated the role of Lithium Chloride (LiCl), a drug largely used for the treatment of neurological disorders, on the two major central myelin gene expression (PLP and MBP) in mouse oligodendrocytes. We show that LiCl enhances the expression of both PLP and MBP, by increasing mRNA amount and promoter activities. We investigated whether Wnt/β-catenin and/or Akt/CREB pathways are modulated by LiCl to regulate myelin gene expression. We showed that β-catenin is required both for PLP and MBP basal promoter activities and for LiCl-induced myelin gene stimulation. Furthermore, while CREB functionality does not influence PLP expression, MBP promoter activity depends on Akt/CREB activation. Finally, we show that LiCl can stimulate oligodendrocyte morphological maturation, and promote remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Our data provide mechanistic evidences that Akt/CREB together with β-catenin participate in the transcriptional control of PLP and MBP exerted by LiCl. Therefore, the use of LiCl to balance between β-catenin and CREB effectors could be considered as an efficient remyelinating strategy.

Keywords: Akt/CREB; Wnt/ β-catenin; lithium chloride; oligodendrocytes; remyelination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / physiopathology
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Demyelinating Diseases / drug therapy
  • Demyelinating Diseases / physiopathology
  • Disease Models, Animal
  • Gene Expression / drug effects
  • Lithium Chloride / pharmacology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin Basic Protein / metabolism*
  • Myelin Proteolipid Protein / genetics
  • Myelin Proteolipid Protein / metabolism*
  • Neuroprotective Agents / pharmacology*
  • Oligodendroglia / drug effects*
  • Oligodendroglia / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Tissue Culture Techniques
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, mouse
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Mbp protein, mouse
  • Myelin Basic Protein
  • Myelin Proteolipid Protein
  • Neuroprotective Agents
  • Plp1 protein, mouse
  • RNA, Messenger
  • Wnt Proteins
  • beta Catenin
  • Proto-Oncogene Proteins c-akt
  • Lithium Chloride