title: Neuronal expression of the transcription factor serum response factor modulates myelination in a mouse multiple sclerosis model.
abstract: 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.
authors: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors: Sofia
authors: S
authors: Anastasiadou
authors: Sophie
authors: S
authors: Liebenehm
authors: Daniela
authors: D
authors: Sinske
authors: Christopher
authors: C
authors: Meyer zu Reckendorf
authors: Barbara
authors: B
authors: Moepps
authors: Alfred
authors: A
authors: Nordheim
authors: Bernd
authors: B
authors: Knöll
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003471:Cuprizone; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology*; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D012333:RNA, Messenger; D026362:Serum Response Factor; D003471:Cuprizone
keywords: SRF; cuprizone; immune response; multiple sclerosis; myelin