title: TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function.
abstract: Traf2 and NcK interacting kinase (TNiK) contains serine-threonine kinase and scaffold domains and has been implicated in cell proliferation and glutamate receptor regulation in vitro. Here we report its role in vivo using mice carrying a knock-out mutation. TNiK binds protein complexes in the synapse linking it to the NMDA receptor (NMDAR) via AKAP9. NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation and TNiK is required for AMPA expression and synaptic function. TNiK also organizes nuclear complexes and in the absence of TNiK, there was a marked elevation in GSK3β and phosphorylation levels of its cognate phosphorylation sites on NeuroD1 with alterations in Wnt pathway signaling. We observed impairments in dentate gyrus neurogenesis in TNiK knock-out mice and cognitive testing using the touchscreen apparatus revealed impairments in pattern separation on a test of spatial discrimination. Object-location paired associate learning, which is dependent on glutamatergic signaling, was also impaired. Additionally, TNiK knock-out mice displayed hyperlocomotor behavior that could be rapidly reversed by GSK3β inhibitors, indicating the potential for pharmacological rescue of a behavioral phenotype. These data establish TNiK as a critical regulator of cognitive functions and suggest it may play a regulatory role in diseases impacting on its interacting proteins and complexes.
authors.affiliation: Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom.
authors.forename: Marcelo P
authors.initials: MP
authors.lastname: Coba
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.forename: Jess
authors.initials: J
authors.lastname: Nithianantharajah
authors.forename: Maksym V
authors.initials: MV
authors.lastname: Kopanitsa
authors.forename: Tim
authors.initials: T
authors.lastname: Indersmitten
authors.forename: Nathan G
authors.initials: NG
authors.lastname: Skene
authors.forename: Ellie J
authors.initials: EJ
authors.lastname: Tuck
authors.forename: David G
authors.initials: DG
authors.lastname: Fricker
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Elsegood
authors.forename: Lianne E
authors.initials: LE
authors.lastname: Stanford
authors.forename: Nurudeen O
authors.initials: NO
authors.lastname: Afinowi
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Saksida
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bussey
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Dell
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
mesh_terms: D000818:Animals; D001245:Association Learning / Q000502:physiology*; D002467:Cell Nucleus / Q000201:enzymology; D003072:Cognition Disorders / Q000201:enzymology* / Q000503:physiopathology; D018891:Dentate Gyrus / Q000201:enzymology* / Q000473:pathology; D004193:Discrimination Learning / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D010641:Phenotype; D010766:Phosphorylation; D057907:Post-Synaptic Density / Q000201:enzymology* / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017603:Signal Detection, Psychological / Q000502:physiology*; D013028:Space Perception / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D018698:Glutamic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; C545105:TNIK protein, mouse; D038362:Glycogen Synthase Kinase 3