Polarizing receptor activation dissociates Fibroblast Growth Factor 2 mediated inhibition of myelination from its neuroprotective potential

Thümmler, K. et al. (2019) Polarizing receptor activation dissociates Fibroblast Growth Factor 2 mediated inhibition of myelination from its neuroprotective potential. Acta Neuropathologica Communications, 7, 212. (doi: 10.1186/s40478-019-0864-6) (PMID:31856924) (PMCID:PMC6923900)

Abstract

Fibroblast growth factor (FGF) signaling contributes to failure of remyelination in multiple sclerosis, but targeting this therapeutically is complicated by its functional pleiotropy. We now identify FGF2 as a factor up-regulated by astrocytes in active inflammatory lesions that disrupts myelination via FGF receptor 2 (FGFR2) mediated activation of Wingless (Wnt) signaling; pharmacological inhibition of Wnt being sufficient to abrogate inhibition of myelination by FGF2 in tissue culture. Using a novel FGFR1-selective agonist (F2 V2) generated by deleting the N-terminal 26 amino acids of FGF2 we demonstrate polarizing signal transduction to favor FGFR1 abrogates FGF mediated inhibition of myelination but retains its ability to induce expression of pro-myelinating and immunomodulatory factors that include Cd93, Lif, Il11, Hbegf, Cxcl1 and Timp1. Our data provide new insights into the mechanistic basis of remyelination failure in MS and identify selective activation of FGFR1 as a novel strategy to induce a neuroprotective signaling environment in multiple sclerosis and other neurological diseases.

• Item Type: Articles
• Additional Information: This work was supported by funding from the United Kingdom Multiple Sclerosis Society; RS McDonald Charitable trust; Naomi Bramson Trust; Gemeinnützige Hertie Stiftung; TENOVUS and the Swiss National Science Foundation (SNF31003A_159528).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Muecklisch, Dr Katja and Cole, Mr John and Lindner, Dr Maren and Linington, Professor Christopher and Edgar, Professor Julia
• Authors: Thümmler, K., Rom, E., Zeis, T., Lindner, M., Brunner, S., Cole, J., Arseni, D., Mücklisch, S., Edgar, J., Schaeren-Wiemers, N., Yayon, A., and Linington, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Acta Neuropathologica Communications
• Publisher: BioMed Central
• ISSN: 2051-5960
• ISSN (Online): 2051-5960
• Copyright Holders: Copyright © The Authors 2019
• First Published: First published in Acta Neuropathologica Communications 7:212
• Publisher Policy: Reproduced under a Creative Commons license