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The Journal of Neuroscience, May 14, 2008, 28(20):5195-5206; doi:10.1523/JNEUROSCI.1180-08.2008

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Development/Plasticity/Repair
Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination

Michele D. Binder,^1,2 Holly S. Cate,^1,2 Anne L. Prieto,³ Dennis Kemper,¹ Helmut Butzkueven,^1,2 Melissa M. Gresle,^1,2 Tania Cipriani,¹ Vilija G. Jokubaitis,¹ Peter Carmeliet,⁴ and Trevor J. Kilpatrick^1,2

¹Howard Florey Institute and ²The Centre for Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia, ³Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, and ⁴Flanders Interuniversitary Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium

Correspondence should be addressed to Trevor J. Kilpatrick, Howard Florey Institute, University of Melbourne, Victoria 3010, Australia. Email: t.kilpatrick{at}hfi.unimelb.edu.au

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 of Axl, Mer, and Gas6 mRNA 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 of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 ± 3.1 vs 11.8 ± 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor 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- (glutathione S-transferase-)-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.

Key words: Gas6; oligodendrocytes; microglia; demyelination; TAM receptor; cuprizone

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Received July 20, 2007; accepted April 4, 2008.

Correspondence should be addressed to Trevor J. Kilpatrick, Howard Florey Institute, University of Melbourne, Victoria 3010, Australia. Email: t.kilpatrick{at}hfi.unimelb.edu.au

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