title: Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction.
abstract: Although the elaborate combination of histone and non-histone protein complexes defines chromatin organization and hence regulates numerous nuclear processes, the role of chromatin organizing proteins remains unexplored at the organismal level. The highly abundant, multifunctional, chromatin-associated protein and transcriptional coactivator positive coactivator 4 (PC4/Sub1) is absolutely critical for life, because its absence leads to embryonic lethality. Here, we report results obtained with conditional PC4 knock-out (PC4(f/f) Nestin-Cre) mice where PC4 is knocked out specifically in the brain. Compared with the control (PC4(+/+) Nestin-Cre) mice, PC4(f/f) Nestin-Cre mice are smaller with decreased nocturnal activity but are fertile and show no motor dysfunction. Neurons in different areas of the brains of these mice show sensitivity to hypoxia/anoxia, and decreased adult neurogenesis was observed in the dentate gyrus. Interestingly, PC4(f/f) Nestin-Cre mice exhibit a severe deficit in spatial memory extinction, whereas acquisition and long term retention were unaffected. Gene expression analysis of the dorsal hippocampus of PC4(f/f) Nestin-Cre mice revealed dysregulated expression of several neural function-associated genes, and PC4 was consistently found to localize on the promoters of these genes, indicating that PC4 regulates their expression. These observations indicate that non-histone chromatin-associated proteins like PC4 play a significant role in neuronal plasticity.
authors.affiliation: From the Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore-560064, India.
authors.forename: Amrutha
authors.initials: A
authors.lastname: Swaminathan
authors.affiliation: the Université de Lyon, Ecole Normale Supérieure de Lyon, Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Delage
authors.affiliation: the Laboratoire de Neurosciences Cognitives et Adaptatives, UMR7364, Université de Strasbourg, F-67000, Strasbourg, France, the UMR 7364, Laboratoire de Neurosciences Cognitives et Adaptatives, CNRS, F-67000, Strasbourg, France, and.
authors.forename: Snehajyoti
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: the Université de Lyon, Ecole Normale Supérieure de Lyon, Department of Biologie, Lyon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Belgarbi-Dutron
authors.affiliation: the Laboratoire de Neurosciences Cognitives et Adaptatives, UMR7364, Université de Strasbourg, F-67000, Strasbourg, France, the UMR 7364, Laboratoire de Neurosciences Cognitives et Adaptatives, CNRS, F-67000, Strasbourg, France, and.
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Cassel
authors.affiliation: the Université de Lyon, Ecole Normale Supérieure de Lyon, Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Martinez
authors.affiliation: the Laboratoire de Neurosciences Cognitives et Adaptatives, UMR7364, Université de Strasbourg, F-67000, Strasbourg, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Cosquer
authors.affiliation: From the Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore-560064, India.
authors.forename: Sujata
authors.initials: S
authors.lastname: Kumari
authors.affiliation: the Université de Lyon, Ecole Normale Supérieure de Lyon, Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Mongelard
authors.affiliation: the Département de Pathologie, Hôpital de Hautepierre, Université de Strasbourg, 67081 Strasbourg, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Lannes
authors.affiliation: the Laboratoire de Neurosciences Cognitives et Adaptatives, UMR7364, Université de Strasbourg, F-67000, Strasbourg, France, the UMR 7364, Laboratoire de Neurosciences Cognitives et Adaptatives, CNRS, F-67000, Strasbourg, France, and.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cassel
authors.affiliation: the Laboratoire de Neurosciences Cognitives et Adaptatives, UMR7364, Université de Strasbourg, F-67000, Strasbourg, France, the UMR 7364, Laboratoire de Neurosciences Cognitives et Adaptatives, CNRS, F-67000, Strasbourg, France, and laurette@unistra.fr.
authors.forename: Anne-Laurence
authors.initials: AL
authors.lastname: Boutillier
authors.affiliation: the Université de Lyon, Ecole Normale Supérieure de Lyon, Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France, philippe.bouvet@ens-lyon.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouvet
authors.affiliation: From the Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore-560064, India, tapas@jncasr.ac.in.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D065852:Spatial Memory / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins
keywords: Knockout; Spatial memory; chromatin structure; gene expression; hypoxia; neurogenesis; transgenic mice