Oligodendroglial fibroblast growth factor receptor 1 gene targeting protects mice from experimental autoimmune encephalomyelitis through ERK/AKT phosphorylation

Abstract

Fibroblast growth factors (FGFs) exert diverse biological effects by binding and activation of specific fibroblast growth factor receptors (FGFRs). FGFs and FGFRs have been implicated in demyelinating pathologies including multiple sclerosis. In vitro activation of the FGF2/FGFR1 pathway results in downregulation of myelin proteins. FGF1, 2 and 9 have been shown to be involved in the pathology of multiple sclerosis. Recent studies on the function of oligodendroglial FGFR1 in a model of toxic demyelination showed that deletion of FGFR1 led to increased remyelination and preservation of axonal density and an increased number of mature oligodendrocytes. In the present study the in vivo function of oligodendroglial FGFR1 was characterized using an oligodendrocyte-specific genetic approach in the most frequently used model of multiple sclerosis the MOG -induced EAE. Oligodendroglial FGFR1 deficient mice (referred to as Fgfr1 ) showed a significantly ameliorated disease course in MOG -induced EAE. Less myelin and axonal loss, and reduced lymphocyte and macrophage/microglia infiltration were found in Fgfr1 mice. The reduction in disease severity in Fgfr1 mice was accompanied by ERK/AKT phosphorylation, and increased expression of BDNF and TrkB. Reduced proinflammatory cytokine and chemokine expression was seen in Fgfr1 mice compared with control mice. Considering that FGFR inhibitors are used in cancer trials, the oligodendroglial FGFR1 pathway may provide a new target for therapy in multiple sclerosis.

The Bu Shen Yi Sui Formula Promotes Axonal Regeneration via Regulating the Neurotrophic Factor BDNF/TrkB and the Downstream PI3K/Akt Signaling Pathway

“…Published research has reported that BDNF and its receptors are increased around lesions in MS, indicating that BDNF participates in focal repair (Stadelmann et al, 2002). Another study showed that BDNF and TrkB are downregulated during MS/EAE (Vacaras et al, 2014; Rajendran et al, 2018). Our previous studies found that the expression of BDNF in the brain and spinal cord is reduced in mice with EAE (Zheng et al, 2013).…”

Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG35‐55‐induced EAE through ERK and Akt signalling

“…In mice, FGFR1 is expressed in both OPCs and differentiated oligodendrocytes, whereas FGFR2 is found only in differentiated oligodendrocytes (10). Findings on the function of FGFR1 in oligodendrocytes are available from two demyelinating disease models (11,12). In a toxic demyelinating mouse model, a cell-specific deletion of FGFR1 in oligodendrocytes caused an increase in myelin thickness and axon diameters (12).…”

“…In a toxic demyelinating mouse model, a cell-specific deletion of FGFR1 in oligodendrocytes caused an increase in myelin thickness and axon diameters (12). To further delineate the cell-specific functions of FGFR1 in oligodendrocytes in MS, we generated an oligodendrocyte cell-specific FGFR1 knockout (Fgfr1 ind−/− mice) and subjected it to MOG 35-55 -induced EAE (11). Our results revealed that Fgfr1 ind−/− mice showed fewer motor deficits, and reduced myelin and axon degeneration (11).…”

Polarizing receptor activation dissociates fibroblast growth factor 2 mediated inhibition of myelination from its neuroprotective potential

“…We propose this concatenation of FGFR1-dependent effects are responsible for the neuroprotective potential of FGF2 in EAE [66], but the relative importance of FGFR1-dependent responses in different cell type remains unclear. FGFR1 expression in oligodendrocytes is reported to suppress disease activity in EAE [61] and enhance remyelination following chronic cuprizone mediated demyelination [92]. However these interpretations should be treated with caution as tamoxifen was used to ablate expression of FGFR1 in these studies.…”