title: Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons.
abstract: 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.
authors.affiliation: Centre for the Study of Neurological Disorders (CSND), Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland 123 Saint Stephen's Green, Dublin 2 Ireland.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: König
authors.forename: Beau J
authors.initials: BJ
authors.lastname: Fenner
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Byrne
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwamborn
authors.forename: Tytus
authors.initials: T
authors.lastname: Bernas
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000818:Animals; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D016220:Fibroblast Growth Factor 1