Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination

Abstract

A key aim of therapy for multiple sclerosis (MS) is to promote the regeneration of oligodendrocytes and remyelination in the central nervous system (CNS). The present study provides evidence that the vitamin K-dependent protein growth arrest specific 6 (Gas6) promotes such repair in in vitro cultures of mouse optic nerve and cerebellum. We first determined expression of Gas6 and TAM (Tyro3, Axl, Mer) receptors in the mouse CNS, with all three TAM receptors increasing in expression through postnatal development, reaching maximal levels in the adult. Treatment of cultured mouse optic nerves with Gas6 resulted in significant increases in oligodendrocyte numbers as well as expression of myelin basic protein (MBP). Gas6 stimulation also resulted in activation of STAT3 in optic nerves as well as downregulation of multiple genes involved in MS development, including matrix metalloproteinase-9 (MMP9), which may decrease the integrity of the blood–brain barrier and is found upregulated in MS lesions. The cytoprotective effects of Gas6 were examined in in vitro mouse cerebellar slice cultures, where lysolecithin was used to induce demyelination. Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining, and Gas6 activated Tyro3 receptor through its phosphorylation. In conclusion, these results demonstrate that Gas6/TAM signaling stimulates the generation of oligodendrocytes and increased myelin production via Tyro3 receptor in the adult CNS, including repair after demyelinating injury. Furthermore, the effects of Gas6 on STAT3 signaling and matrix MMP9 downregulation indicate potential glial cell repair and immunoregulatory roles for Gas6, indicating that Gas6-TAM signaling could be a potential therapeutic target in MS and other neuropathologies.

Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure

“…While Axl –/– mice show no differences in the number of myelinated axons in the corpus callosum at 3‐weeks recovery, significantly fewer myelinated axons are observed in DKO relative to WT mice, suggesting that deletion of Axl alone does not directly impair remyelination (Hoehn et al, ). The ability of Axl –/– mice to efficiently remyelinate axons at 3‐weeks recovery while Gas6 –/– and DKO mice show impairment in remyelination provide further support of a role for Gas6‐Tyro3 signaling in remyelination (Akkermann et al, ; Goudarzi et al, ; Prieto, O'Dell, Varnum, & Lai, ; Prieto et al, ).…”

“…The importance of both Gas6 and Axl signaling has been well documented in the CNS during autoimmune and demyelinating conditions such as MS and in mice during myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone toxicity model (Akkermann et al, 2017;Binder et al, 2008;Goudarzi, Rivera, Butt, & Hafizi, 2016;Gruber et al, 2014;Hoehn et al, 2008;Shankar et al, 2006;Tsiperson, Li, Schwartz, Raine, & Shafit-Zagardo, 2010;Weinger et al, 2011;Weinger, Omari, Marsden, Raine, & Shafit-Zagardo, 2009). Our study of TAM proteins in MS lesions showed elevated levels of soluble Axl and MerTK, and increased levels of proteins associated with Axl and MerTK solubilization that is not seen in normal appearing white matter from the same individuals (Weinger et al, 2009).…”

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

“…( Figure 2B). In addition to its role in viral entry, GAS6 promotes oligodendrogenesis and myelination in the adult nervous system (52) and acts as a neurotrophic factor during hippocampal development (53). NECTIN2 is necessary for neuronal and glial survival (54).…”

Аnti-inflammatory effects of vitamin K on women's health

“…Выявлено влияние витамина K на когнитивную функцию, его положительные эффекты при болезни Альцгеймера. Среди ВK-зависимых белков наибольшими нейротропными свойствами, реализуемыми в структурах нервной системы, обладает Gas6: он участвует в процессах миелинизации, хемотаксисе, митогенезе, клеточном росте, регуляции функции олигодендроцитов, шванновских клеток, микроглии [22]. Интересно, что экспрессия гена белка Gas6 наблюдается еще на ранних стадиях эмбриогенеза, что указывает на его роль в развитии нервной системы плода [21].…”