FGFR1 is a negative regulator of LINGO-1 expression in EAE (P2.194)

Objective: The objective of this study is to evaluate the interaction between oligodendroglial Fgfr1 and LINGO-1 in EAE. Background: Failure of remyelination is a key feature of multiple sclerosis (MS). LINGO-1, TGF-β, SEMA3A and FGF2 are known inhibitors of remyelination in MS and EAE. Data suggest that FGFR1 negatively regulates myelination in demyelinating pathologies. It is unknown which factors regulate LINGO-1 expression. LINGO-1 is expressed in oligodendrocytes, it disturbs oligodendrocyte differentiation and myelination via upregulation of NgR1 and downregulation of the AKT signaling pathway. We hypothesized that LINGO-1 expression is mediated by oligodendroglial Fgfr1 in EAE. Design/Methods: Tamoxifen injectable PLP-Cre-mediated deletion of Fgfr1 in oligodendrocytes was done in four-week-old female mice. EAE was induced in eight to twelve-week-old oligodendroglial Fgfr1 knockout mice (Fgfr1ind-/-) and controls. Spinal cord tissue was analyzed for various myelin inhibitors at days 18-20 p.i. (acute) and 62 p.i. (chronic phase) by RT-PCR. Furthermore ERK and AKT phosphorylation was studied by western blot. Results: Fgfr1ind-/- mice showed reduced expression of the myelin inhibitors LINGO-1 (P ≤ 0.05) and a trend towards reduction of FGF2 (P = 0.071) in chronic EAE. There was no regulation of SEMA3A and TGF-β in chronic EAE. Also, there was no regulation of these myelin inhibitors in acute EAE. In chronic EAE Fgfr1ind-/- mice showed increased expression of ERK (P ≤ 0.05) and AKT (P ≤ 0.05) phosphorylation. Fgfr1 expression was reduced in Fgfr1ind-/- mice in both acute (P ≤ 0.05) and chronic EAE (P ≤ 0.05). Conclusions: Our results suggest that LINGO-1 expression is mediated by oligodendroglial Fgfr1 in EAE. The molecular mechanism underlying the reduced expression of LINGO-1 in Fgfr1ind-/- mice might be due to activation of FGFR1 downstream signaling. Blocking of Fgfr1 in oligodendrocytes may enhance remyelination through inhibition of the LINGO-1 complex. This study was supported by MERCK Serono.