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Updated: Jul 5, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced
Michele D Binder1, Holly S Cate, Anne L Prieto
1Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
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 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 alpha mRNA expression was reduced approximately 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-pi (glutathione S-transferase-pi)-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.
Insights
Growth arrest gene 6 (Gas6) and TAM receptors are crucial for oligodendrocyte survival and regulating microglial responses in demyelination. Gas6 deficiency exacerbates CNS damage and oligodendrocyte loss.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- The TAM family (Tyro3, Axl, Mer) of receptor tyrosine kinases are expressed in the nervous system, including by oligodendrocytes.
- Oligodendrocytes are vital for myelinating the central nervous system (CNS).
- Gas6 (growth arrest gene 6) is the primary ligand for TAM receptors.
Purpose of the Study:
- To investigate the role of TAM receptors and Gas6 in the cuprizone model of demyelination.
- To understand their influence on oligodendrocyte survival and microglial activation.
Main Methods:
- Examined mRNA expression of Axl, Mer, Gas6, and Tyro3 in the corpus callosum during cuprizone-induced demyelination.
- Assessed oligodendrocyte survival and microglial activation markers in vitro.
- Analyzed demyelination, oligodendrocyte loss, and microglial response in Gas6 knockout mice subjected to cuprizone challenge.
Main Results:
- Axl, Mer, and Gas6 mRNA expression increased with microglial proliferation during demyelination.
- Tyro3 expression decreased, correlating with oligodendrocyte loss.
- Gas6 promoted oligodendrocyte survival and reduced microglial activation (TNF-alpha mRNA).
- Gas6-/- mice showed increased demyelination, oligodendrocyte loss, and microglial activation in the corpus callosum.
Conclusions:
- TAM receptor activation by Gas6 influences oligodendrocyte survival independently.
- Gas6 signaling modulates the microglial response to CNS damage.
- Targeting Gas6/TAM signaling may offer therapeutic strategies for demyelinating diseases.
