TY - JOUR
T1 - Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination
AU - Binder, Michele D.
AU - Cate, Holly S.
AU - Prieto, Anne L.
AU - Kemper, Dennis
AU - Butzkueven, Helmut
AU - Gresle, Melissa M.
AU - Cipriani, Tania
AU - Jokubaitis, Vilija G.
AU - Carmeliet, Peter
AU - Kilpatrick, Trevor J.
PY - 2008/5/14
Y1 - 2008/5/14
N2 - 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 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 (glutathione S-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.
AB - 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 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 (glutathione S-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.
KW - Cuprizone
KW - Demyelination
KW - Gas6
KW - Microglia
KW - Oligodendrocytes
KW - TAM receptor
UR - http://www.scopus.com/inward/record.url?scp=45549108475&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1180-08.2008
DO - 10.1523/JNEUROSCI.1180-08.2008
M3 - Article
C2 - 18480276
AN - SCOPUS:45549108475
VL - 28
SP - 5195
EP - 5206
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 20
ER -