Animals, Fibroblast Growth Factor 1, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Neurons, Phosphorylation, Rats, Rats, Sprague-Dawley, Signal Transduction, Transfection
Neuronal survival and plasticity critically depend on constitutive activity of the transcription factor nuclear factor-κB (NF-κB). We here describe a role for a small intracellular fibroblast growth factor homologue, the fibroblast growth factor homologous factor 1 (FHF1/FGF12), in the regulation of NF-κB activity in mature neurons. FHFs have previously been described to control neuronal excitability, and mutations in FHF isoforms give rise to a form of progressive spinocerebellar ataxia. Using a protein-array approach, we identified FHF1b as a novel interactor of the canonical NF-κB modulator IKKγ/NEMO. Co-immunoprecipitation, pull-down and GAL4-reporter experiments, as well as proximity ligation assays, confirmed the interaction of FHF1 and NEMO and demonstrated that a major site of interaction occurred within the axon initial segment. Fhf1 gene silencing strongly activated neuronal NF-κB activity and increased neurite lengths, branching patterns and spine counts in mature cortical neurons. The effects of FHF1 on neuronal NF-κB activity and morphology required the presence of NEMO. Our results imply that FHF1 negatively regulates the constitutive NF-κB activity in neurons.
Physics | Physiology
Konig HG, Fenner BJ, Byrne JC, Schwamborn RF, Bernas T, Jefferies CA, Prehn JHM. Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons. Journal of Cell Science. 2012;125(24):6058-70.