Neuronal expression of the transcription factor serum response factor modulates myelination in a mouse multiple sclerosis model

• Published in: Glia 2015-06, Vol.63 (6), p.958-976
• Main Authors: Anastasiadou, Sofia, Liebenehm, Sophie, Sinske, Daniela, Meyer zu Reckendorf, Christopher, Moepps, Barbara, Nordheim, Alfred, Knöll, Bernd
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - pathology; Astrocytes - physiology; Cells, Cultured; Chemokine CCL2 - metabolism; Cuprizone; Disease Models, Animal; immune response; Male; Medical research; Mice, Inbred C57BL; Mice, Transgenic; Microglia - pathology; Microglia - physiology; Multiple sclerosis; Multiple Sclerosis - pathology; Multiple Sclerosis - physiopathology; myelin; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelin Sheath - physiology; Neurons; Neurons - metabolism; Neurons - pathology; Oligodendroglia - pathology; Oligodendroglia - physiology; RNA, Messenger - metabolism; Rodents; Serum Response Factor - genetics; Serum Response Factor - metabolism; SRF; Transcription factors
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22794

In multiple sclerosis (MS), neurons in addition to inflammatory cells are now considered to mediate disease origin and progression. So far, molecular and cellular mechanisms of neuronal MS contributions are poorly understood. Herein we analyzed whether neuron‐restricted signaling by the neuroprotective transcription factor serum response factor (SRF) modulates de‐ and remyelination in a rodent MS model. In the mouse cuprizone model, neuron‐ (Srf flox/flox;CaMKCreERT2) but not glia‐specific (Srf flox/flox;PlpCreERT2) SRF depletion impaired demyelination suggesting impaired debris clearance by astrocytes and microglia. This supports an important role of SRF expression in neurons but not oligodendrocytes in de‐ and remyelination. During remyelination, NG2‐ and OLIG2‐positive cells of the oligodendrocyte lineage as well as de novo mRNA synthesis of myelin genes were also reduced in neuron‐specific Srf mutants. Using the stripe assay, we demonstrate that cortices of cuprizone‐fed wild‐type mice elicited astrocyte and microglia activation whereas this was abrogated in cuprizone‐fed neuron‐specific Srf mutants. We identified CCL chemokines (e.g. CCL2) as neuron‐derived SRF‐regulated paracrine signals rescuing immune cell activation upon neuronal SRF deletion. In summary, we uncovered important roles of neurons and neuronally expressed SRF in MS associated de‐ and remyelination. GLIA 2015;63:958–976 Main points Neuron but not glia‐restricted SRF ablation stimulates myelin clearance and remyelination in cuprizone mediated demyelination. Neuronal SRF is involved astrocyte activation and microglia mediated myelin phagocytosis potentially via CCL chemokines.