title: Deficiency of Cks1 Leads to Learning and Long-Term Memory Defects and p27 Dependent Formation of Neuronal Cofilin Aggregates.
abstract: In mitotic cells, the cyclin-dependent kinase (CDK) subunit protein CKS1 regulates S phase entry by mediating degradation of the CDK inhibitor p27. Although mature neurons lack mitotic CDKs, we found that CKS1 was actively expressed in post-mitotic neurons of the adult hippocampus. Interestingly, Cks1 knockout (Cks1-/-) mice exhibited poor long-term memory, and diminished maintenance of long-term potentiation in the hippocampal circuits. Furthermore, there was neuronal accumulation of cofilin-actin rods or cofilin aggregates, which are associated with defective dendritic spine maturation and synaptic loss. We further demonstrated that it was the increased p27 level that activated cofilin by suppressing the RhoA kinase-mediated inhibitory phosphorylation of cofilin, resulting in the formation of cofilin aggregates in the Cks1-/- neuronal cells. Consistent with reports that the peptidyl-prolyl-isomerase PIN1 competes with CKS1 for p27 binding, we found that inhibition of PIN1 diminished the formation of cofilin aggregates through decreasing p27 levels, thereby activating RhoA and increasing cofilin phosphorylation. Our results revealed that CKS1 is involved in normal glutamatergic synapse development and dendritic spine maturation in adult hippocampus through modulating p27 stability.
authors.affiliation: Eukaryotic Chromatin Dynamics Group, MRC Clinical Sciences Centre, Imperial College Hammersmith Campus, London W12 0NN, UK.|Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.|Current address: Epigenetic Regulation and Chromatin Architecture Group , Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine , Robert-Rössle Strasse, Berlin-Buch 13125, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kukalev
authors.affiliation: Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.|Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Yiu-Ming
authors.initials: YM
authors.lastname: Ng
authors.affiliation: Genome Damage and Stability Centre , School of Life Sciences , University of Sussex , Falmer, Sussex BN1 9RQ , UK.
authors.forename: Limei
authors.initials: L
authors.lastname: Ju
authors.affiliation: Genome Damage and Stability Centre , School of Life Sciences , University of Sussex , Falmer, Sussex BN1 9RQ , UK.
authors.forename: Amal
authors.initials: A
authors.lastname: Saidi
authors.affiliation: Eukaryotic Chromatin Dynamics Group , MRC Clinical Sciences Centre , Imperial College Hammersmith Campus , London W12 0NN , UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lane
authors.affiliation: Eukaryotic Chromatin Dynamics Group , MRC Clinical Sciences Centre , Imperial College Hammersmith Campus , London W12 0NN , UK.
authors.forename: Angeles
authors.initials: A
authors.lastname: Mondragon
authors.affiliation: Microscopy Facility , MRC Clinical Sciences Centre , Imperial College Hammersmith Campus , London W12 0NN , UK.
authors.forename: Dirk
authors.initials: D
authors.lastname: Dormann
authors.affiliation: School of Psychology , University of Sussex , Sussex, Brighton BN1 9QG , UK.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Walker
authors.affiliation: Department of Medical and Molecular Genetics , King's College London School of Medicine , Guy's Hospital , Great Maze Pond , London SE1 9RT , UK.
authors.forename: William
authors.initials: W
authors.lastname: Grey
authors.affiliation: Division of Neurology , Department of Medicine , University of Hong Kong , Hong Kong.
authors.forename: Philip Wing-Lok
authors.initials: PW
authors.lastname: Ho
authors.affiliation: School of Psychology , University of Sussex , Sussex, Brighton BN1 9QG , UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Stephens
authors.affiliation: Genome Damage and Stability Centre , School of Life Sciences , University of Sussex , Falmer, Sussex BN1 9RQ , UK.
authors.forename: Antony M
authors.initials: AM
authors.lastname: Carr
authors.affiliation: Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK.|Current address: Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, Szeged H-6726, Hungary.
authors.forename: Karri
authors.initials: K
authors.lastname: Lamsa
authors.affiliation: Division of Haematology , Department of Medicine , The University of Hong Kong , Hong Kong.
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
authors.affiliation: Eukaryotic Chromatin Dynamics Group, MRC Clinical Sciences Centre, Imperial College Hammersmith Campus, London W12 0NN, UK.|Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Veronica P C C
authors.initials: VPCC
authors.lastname: Yu
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D049229:Dendritic Spines; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D017774:Long-Term Potentiation; D008297:Male; D008569:Memory Disorders / Q000378:metabolism* / Q000473:pathology; D057567:Memory, Long-Term; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D066329:Protein Aggregates; D065853:Spatial Learning
chemical_list: D051339:Actin Depolymerizing Factors; D066329:Protein Aggregates; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C474110:Cks1 protein, mouse
keywords: RhoA; cyclin-dependent kinase; hippocampus; long-term potentiation; synaptic plasticity