Regulation of serum response factor by miRNA‐200 and miRNA‐9 modulates oligodendrocyte progenitor cell differentiation

Abstract

Serum response factor (SRF) is a transcription factor that transactivates actin associated genes, and has been implicated in oligodendrocyte (OL) differentiation. To date, it has not been investigated in cerebral ischemia. We investigated the dynamics of SRF expression after stroke in vivo and the role of SRF in oligodendrocyte differentiation in vitro. Using immunohistochemistry, we found that SRF was upregulated in OLs and OL precursor cells (OPCs) after stroke. Moreover, upregulation of SRF was concurrent with downregulation of the microRNAs (miRNAs) miR-9 and the miR-200 family in the ischemic white matter region, the corpus callosum. Inhibition of SRF activation by CCG-1423, a specific inhibitor of SRF function, blocked OPCs from differentiating into OLs. Over-expression of miR-9 and miR-200 in cultured OPCs suppressed SRF expression and inhibited OPC differentiation. Moreover, co-expression of miR-9 and miR-200 attenuated activity of a luciferase reporter assay containing the Srf 3′ untranslated region (UTR). Collectively, this study is the first to show that stroke upregulates SRF expression in OPCs and OLs, and that SRF levels are mediated by miRNAs and regulate OPC differentiation.

Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3+ T-lymphocyte expression in a relapsing–remitting model of multiple sclerosis in rats

“…Considering the pathogenic role of toll like receptors in multiple sclerosis, TLR2 was observed to be highly expressed in brain tissues of the present model making it a logical target for therapeutic intervention in MS. Preclinical studies showed that TLR2 was highly expressed in oligodendrocytes from MS lesions, and that TLR2-specific agonists (but not TLR4 or TLR5 agonists) inhibit the maturation of cultured oligodendrocyte progenitor cells (OPCs) (Sloane et al, 2010). The lack of those OPCs and subsequent lack of differentiated oligodendrocytes is associated with a loss of myelination and impairment of neurological functions (Buller et al, 2012). The TLR signaling could be considered an important linker in the immuneproinflammatory cascade with production of Th1-type cytokines and aggravation of inflammation (Marta, 2009).…”

Targeted Stage-Specific Inflammatory microRNA Profiling in Urine During Disease Progression in Experimental Autoimmune Encephalomyelitis: Markers of Disease Progression and Drug Response

“…Indeed, miR-155-5p detected in the present study in the urine, plasma and SC at the preonset stage in EAE mice is probably one of the first and most frequent miRNA associated with the inflammatory response (Zhang et al 2014) in EAE pathology. In addition, miR-9-5p, miR-200c-3p and miR16-5p significantly increased in urine exosomes and have a possible CNS role since miR-9 and miR200c regulate oligodendrocyte progenitor differentiation (Buller et al 2012). Putative targets of miR-16 include Bcl-2 (Cimmino et al 2005) and myelin transcription factor (Myt1l) genes (http://www.umm.uni-heidelberg.de/apps/zmf/ mirwalk/).…”

Exosomes in stroke pathogenesis and therapy

“…Stroke-induced limited axonal sprouting and remyelination in the periinfarct region are also regulated by miRNAs. In vitro and in vivo studies showed that stroke-induced downregulation of miR-9 and miR200b expression in white matter mediates remyelination (55). Chondroitin sulfate proteoglycans (CSPGs) produced by reactive astrocytes inhibit axonal regrowth (56).…”