Identifying factors that support the viability of oligodendrocytes and enhance myelination is essential for a more complete understanding of normal CNS maturation, and the events following a demyelinating assault such as an inflammatory attack that occurs in Multiple Sclerosis. Toward that end, our laboratory initiated microarray studies to identify genes expressed in human fetal O4+ immunopanned oligodendrocytes at multiple gestational weeks. Among the cDNAs identified were members of the receptor tyrosine kinase family, Axl, Rse, and Mer. The ligand, vitamin K-dependent growth-arrest specific protein 6 (gas6), activates the Axl, Rse, and Mer receptors and protects against growth factor withdrawal and other stressors by signaling through the PI3 kinase/Akt survival pathway. Our recent studies with oligodendrocyte cultures, oligodendrocyte/DRG co-cultures, and the cuprizone model have supported our hypothesis that the gas6/Axl/PI3 kinase/Akt signaling pathway functions in oligodendrocyte survival. Also, this pathway has important relevance to central nervous system (CNS) development and disorders involving inflammation, and myelination. Our preliminary data demonstrate that the addition of recombinant human gas6 (rhgas6) to rat oligodendrocyte/DRG co-cultures enhances myelination of axons; and addition of the decoy Axl-Fc diminishes myelination relative to the untreated cultures and the rhgas6-treated cultures. In addition, deletion of the Axl receptor alters remyelination 3 weeks following the removal of cuprizone, an oligodendrocyte toxin fed to mice for 6 weeks prior to assessing remyelination. This proposal will investigate in vivo the role of rhgas6 in protecting oligodendrocytes from cell death, and enhancing remyelination within the cuprizone mouse model paradigm. The hypothesis to be tested in this proposal is that exogenous gas6 administration directly to the corpus callosum can protect oligodendrocytes from cuprizone toxicity; and enhance remyelination during the recovery phase following cuprizone withdrawal. A mini-pump will be utilized to administer rhgas6 at two different time points.
In Specific Aim #1 we will determine whether direct administration of rhgas6 to the corpus callosum of wildtype (WT) C57BL6J mice 1.5 weeks after the initiation of cuprizone treatment protects oligodendrocytes from cuprizone-induced cell death at week 3.5, a time-point when oligodendrocyte cell loss is clearly detectable.
In Specific Aim #2 we will determine whether following cuprizone withdrawal, direct administration of rhgas6 to the corpus callosum of WT mice for two weeks enhances oligodendrocyte maturation and remyelination. These studies will provide insight into signaling processes that protect oligodendrocytes from dysfunction and/or death, and perhaps aid in remyelination in vivo. These studies have potential for translational research in diseases such as Multiple Sclerosis and spinal cord injury.
The ability to achieve successful myelination is a priority for movement and higher brain function. To obtain successful remyelination following injury would positively impact upon the public health of individuals of all ages and dramatically improve the quality of their lives. Based upon our published and ongoing studies demonstrating that growth arrest specific protein 6 (gas6) enhances oligodendrocyte survival, maturation, and possibly myelination, this timely study examining the role of rhgas6 in a mouse model of demyelination/remyelination should have implications for human demyelinating diseases. ? ? ?
| Tsiperson, Vladislav; Gruber, Ross C; Goldberg, Michael F et al. (2013) Suppression of inflammatory responses during myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis is regulated by AKT3 signaling. J Immunol 190:1528-39 |
| Weinger, Jason G; Brosnan, Celia F; Loudig, Olivier et al. (2011) Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis. J Neuroinflammation 8:49 |
| Tsiperson, Vladislav; Li, Xiaosong; Schwartz, Gary J et al. (2010) GAS6 enhances repair following cuprizone-induced demyelination. PLoS One 5:e15748 |
| Weinger, Jason G; Omari, Kakuri M; Marsden, Kurt et al. (2009) Up-regulation of soluble Axl and Mer receptor tyrosine kinases negatively correlates with Gas6 in established multiple sclerosis lesions. Am J Pathol 175:283-93 |
