FGF9 induces neurite outgrowth upon ERK signaling in knock-in striatal Huntington's disease cells

Life Sci. 2021 Feb 15;267:118952. doi: 10.1016/j.lfs.2020.118952. Epub 2020 Dec 29.

Abstract

Aims: Huntington's disease (HD) is a neurodegenerative disease that causes deficits in neurite outgrowth, which suggests that enhancement of neurite outgrowth is a potential direction by which to improve HD. Our previous publications showed that fibroblast growth factor 9 (FGF9) provides anti-apoptosis and anti-oxidative functions in striatal cell models of HD through the extracellular signal-regulated kinases (ERK) pathway, and FGF9 also stimulates cytoskeletons to enhance neurite outgrowth via nuclear factor kappa B (NF-kB) signaling. In this study, we further demonstrate the importance of the ERK pathway for the neurite outgrowth induced by FGF9 in HD striatal models.

Materials and methods: FGF9 was treated with ERK (U0126) or NF-kB (BAY11-7082) inhibitors in STHdhQ7/Q7 and STHdhQ111/Q111 striatal knock-in cell lines to examine neurite outgrowth, cytoskeletal markers, and synaptic proteins via immunofluorescence staining and Western blotting. NF-kB activity was analyzed by NF-kB promoter reporter assay.

Key findings: Here, we show that suppression of ERK signaling significantly inhibits FGF9-induced neurite outgrowth, cytoskeletal markers, and synaptic proteins in HD striatal cells. In addition, we also show suppression of ERK signaling significantly decreases FGF9-induced NF-kB activation, whereas suppression of NF-kB does not decrease FGF9-induced ERK signaling. These results suggest that FGF9 activates ERK signaling first, stimulates NF-kB upregulation, and then enhances neurite outgrowth in HD striatal cells.

Significance: We elucidate the more detailed mechanisms of neurite outgrowth enhanced by FGF9 in these HD striatal cells. This study may provide insights into targeting neurite outgrowth for HD therapy.

Keywords: ERK signaling; Fibroblast growth factor 9; Huntington's disease; NF-κB signaling; Neurite outgrowth.

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Cell Line
  • Cells, Cultured
  • Corpus Striatum / metabolism
  • Enzyme Inhibitors / pharmacology
  • Fibroblast Growth Factor 9 / antagonists & inhibitors
  • Fibroblast Growth Factor 9 / metabolism*
  • Fibroblast Growth Factor 9 / pharmacology*
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Neurites / drug effects
  • Neurites / metabolism*
  • Neuronal Outgrowth / physiology
  • Nitriles / pharmacology
  • Nuclear Proteins / metabolism
  • Oxidative Stress / drug effects
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Sulfones / pharmacology

Substances

  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Butadienes
  • Enzyme Inhibitors
  • Fibroblast Growth Factor 9
  • Htt protein, mouse
  • Huntingtin Protein
  • NF-kappa B
  • Nitriles
  • Nuclear Proteins
  • Recombinant Proteins
  • Sulfones
  • U 0126