title: FGF2 and FGFR1 signaling regulate functional recovery following cuprizone demyelination.
abstract: In demyelinating diseases, such as multiple sclerosis, remyelination offers the potential to recover function of viable denuded axons by restoring saltatory conduction and/or protecting from further damage. Mice with genetic reduction of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) exhibit dramatically improved remyelination following experimental demyelination with cuprizone. The current studies are the first to test neurobehavioral outcomes with these gene deletions that improved remyelination. The cuprizone protocols used did not produce overt abnormalities but did reduce bilateral sensorimotor coordination (complex wheel task) and increase sociability (two chamber apparatus with novel mouse). A significant effect of genotype was observed on the complex wheel task but not in the sociability apparatus. Specifically, complex wheel velocities for Fgf2 nulls improved significantly after removal of cuprizone from the diet. This improvement in Fgf2 null mice occurred following either acute (6 weeks) or chronic (12 weeks) demyelination. Plp/CreERT:Fgfr1(fl/fl) mice administered tamoxifen at 10 weeks of cuprizone treatment to induce Fgfr1 knockdown also showed improved recovery of running velocities on the complex wheels. Therefore, constitutive deletion of Fgf2 or Fgfr1 knockdown in oligodendrocyte lineage cells is sufficient to overcome impairment of sensorimotor coordination after cuprizone demyelination.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Mierzwa
authors.forename: Yong-Xing
authors.initials: YX
authors.lastname: Zhou
authors.forename: Norah
authors.initials: N
authors.lastname: Hibbits
authors.forename: Adam C
authors.initials: AC
authors.lastname: Vana
authors.forename: Regina C
authors.initials: RC
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D007398:Interpersonal Relations; D051379:Mice; D008822:Mice, Transgenic; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016222:Fibroblast Growth Factor 2; D003471:Cuprizone; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Corpus callosum; Cup; FGF2; FGFR1; Fgf2; Fgfr1; Growth factor; MOG; MS; Multiple sclerosis; OLCs; Plp/CreERT; Remyelination; Sociability; Tam; Wheel activity; cuprizone; fibroblast growth factor 2 ligand; fibroblast growth factor receptor 1; fl; floxed gene; gene encoding murine fibroblast growth factor 2; gene encoding murine fibroblast growth factor receptor 1; multiple sclerosis; myelin oligodendrocyte protein; oligodendrocyte lineage cells; tamoxifen; transgene encoding the murine proteolipid protein promoter driving Cre recombinase fused to mutated estrogen receptor