Back to Search Start Over

Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination

Authors :
Michele D. Binder
Tania Cipriani
Vilija Jokubaitis
Holly S. Cate
Helmut Butzkueven
Dennis Kemper
Peter Carmeliet
Trevor J. Kilpatrick
Melissa Gresle
Anne L. Prieto
Publication Year :
2008
Publisher :
Society for Neuroscience, 2008.

Abstract

The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles ofAxl,Mer, andGas6mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression ofTyro3decreased, correlating with the loss of oligodendrocytes. Gas6 both promotedin vitrosurvival of oligodendrocytes (39.3 ± 3.1 vs 11.8 ± 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor α mRNA expression was reduced ∼48%). In Gas6−/−mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-π (glutathioneS-transferase-π)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6−/−mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6−/−mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....341607194115bae33edefac100100c29