title: 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.
authors.affiliation: School of Pharmacy and Biomedical Sciences, Institute of Biomedical and Biomolecular Science, University of Portsmouth, UK.
authors.forename: Salman
authors.initials: S
authors.lastname: Goudarzi
authors.affiliation: School of Pharmacy and Biomedical Sciences, Institute of Biomedical and Biomolecular Science, University of Portsmouth, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rivera
authors.affiliation: School of Pharmacy and Biomedical Sciences, Institute of Biomedical and Biomolecular Science, University of Portsmouth, UK.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Butt
authors.affiliation: School of Pharmacy and Biomedical Sciences, Institute of Biomedical and Biomolecular Science, University of Portsmouth, UK sassan.hafizi@port.ac.uk.
authors.forename: Sassan
authors.initials: S
authors.lastname: Hafizi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D020278:Demyelinating Autoimmune Diseases, CNS / Q000139:chemically induced*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008244:Lysophosphatidylcholines / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D009900:Optic Nerve / Q000166:cytology / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C112200:CDC40 protein, human; D018797:Cell Cycle Proteins; D008244:Lysophosphatidylcholines; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D000072260:RNA Splicing Factors; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: TAM receptors; Tyro3; multiple sclerosis; myelin; oligodendrocyte; receptor tyrosine kinase