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.

SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model

“…Herein, we show for the first time the role of SRF in pilocarpine-evoked SE occurrence. Similarly, SRF was so far not associated with epileptiform hippocampal sclerosis, despite reported functions in related processes such as neurodegeneration [32, 33], axon growth, pathfinding and regeneration [34–39] as well as inflammation [40]. Employing adult SRF ablation in glutamatergic forebrain neurons ( Srf CaMKCreERT2 ), we show here decreased epilepsy associated neurodegeneration, mossy fiber sprouting and inflammation.…”

“…In this study we employed forebrain specific deletion of SRF in glutamatergic neurons via a tamoxifen inducible Cre recombinase driven by Camk2a promoter [40]. At the age of seven to 8 weeks, mice were injected five times with tamoxifen and analyzed 2 weeks thereafter (Fig.…”

“…1b, c). In addition, SRF is depleted from the cortex and striatum [40]. In control mice experiencing an SE for 40 min, Srf mRNA levels were elevated (Fig.…”

“…After pilocarpine injection, all animals were observed for a time period of 4 h to assess severity and duration of behavioral seizures. Pilocarpine-induced seizures were classified based on the Racine scheme as described before [40], i.e. stage 1: immobility, rigid posture; stage 2: repetitive movements, head bobbing; stage 3: motor seizure with forelimb clonus; stage 4: severe seizures with rearing without falling; stage 5: severe seizures with rearing and falling or jumping; SE was defined by continuous seizure activity for at least 10 min without full recovery between seizures.…”

Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury

“…Electroporation of DRG neurons was performed with 3 µg DNA and 100 µl electroporation solution (Mirus). The CCL2-Cherry expression vector was described previously [45]. …”