Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination

Ben Emery, Holly S. Cate, Mark Marriott, Tobias Merson, Michele D. Binder, Cameron Snell, Pik Ying Soo, Simon Murray, Ben Croker, Jian Guo Zhang, Warren S. Alexander, Helen Cooper, Helmut Butzkueven, Trevor J. Kilpatrick

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Enhancement of oligodendrocyte survival through activation of leukemia inhibitory factor receptor (LIFR) signaling is a candidate therapeutic strategy for demyelinating disease. However, in other cell types, LIFR signaling is under tight negative regulation by the intracellular protein suppressor of cytokine signaling 3 (SOCS3). We, therefore, postulated that deletion of the SOCS3 gene in oligodendrocytes would promote the beneficial effects of LIFR signaling in limiting demyelination. By studying wild-type and LIF-knockout mice, we established that SOCS3 expression by oligodendrocytes was induced by the demyelinative insult, that this induction depended on LIF, and that endogenously produced LIF was likely to be a key determinant of the CNS response to oligodendrocyte loss. Compared with wild-type controls, oligodendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3. Moreover, these SOCS3-deficient mice were protected against cuprizone-induced oligodendrocyte loss relative to wild-type animals. These results indicate that modulation of SOCS3 expression could facilitate the endogenous response to CNS injury.

Original languageEnglish (US)
Pages (from-to)7859-7864
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number20
DOIs
StatePublished - May 16 2006
Externally publishedYes

Keywords

  • Conditional knockout
  • Cuprizone
  • Oligodendrocyte
  • SOCS3
  • Signal transduction

ASJC Scopus subject areas

  • General

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