title: Mosaic expression of Atrx in the mouse central nervous system causes memory deficits.
abstract: The rapid modulation of chromatin organization is thought to play a crucial role in cognitive processes such as memory consolidation. This is supported in part by the dysregulation of many chromatin-remodelling proteins in neurodevelopmental and psychiatric disorders. A key example is ATRX, an X-linked gene commonly mutated in individuals with syndromic and nonsyndromic intellectual disability. The consequences of Atrx inactivation for learning and memory have been difficult to evaluate because of the early lethality of hemizygous-null animals. In this study, we evaluated the outcome of brain-specific Atrx deletion in heterozygous female mice. These mice exhibit a mosaic pattern of ATRX protein expression in the central nervous system attributable to the location of the gene on the X chromosome. Although the hemizygous male mice die soon after birth, heterozygous females survive to adulthood. Body growth is stunted in these animals, and they have low circulating concentrations of insulin growth factor 1. In addition, they are impaired in spatial, contextual fear and novel object recognition memory. Our findings demonstrate that mosaic loss of ATRX expression in the central nervous system leads to endocrine defects and decreased body size and has a negative impact on learning and memory.
authors.affiliation: Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada.|Departments of Paediatrics, Biochemistry and Oncology, Schulich School of Medicine and Dentistry, the University of Western Ontario, Victoria Research Laboratories, London, Ontario N6A 3K7, Canada.
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Tamming
authors.affiliation: Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, Ontario N6A 3K7, Canada.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Siu
authors.affiliation: Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada.|Departments of Paediatrics, Biochemistry and Oncology, Schulich School of Medicine and Dentistry, the University of Western Ontario, Victoria Research Laboratories, London, Ontario N6A 3K7, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, Ontario N6A 3K7, Canada.|Department of Anatomy and Cell Biology and Robarts Research Institute, the University of Western Ontario, London, Ontario N6A 3K7, Canada.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, Ontario N6A 3K7, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.affiliation: Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada nberube@uwo.ca.|Departments of Paediatrics, Biochemistry and Oncology, Schulich School of Medicine and Dentistry, the University of Western Ontario, Victoria Research Laboratories, London, Ontario N6A 3K7, Canada.
authors.forename: Nathalie G
authors.identifier: 0000-0003-1948-8715
authors.initials: NG
authors.lastname: Bérubé
mesh_terms: D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005239:Fear; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D048788:Growth and Development; D018737:Hand Strength; D006579:Heterozygote; D006614:Hindlimb / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D018782:Maze Learning; D008569:Memory Disorders / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D008570:Memory, Short-Term; D051379:Mice; D009030:Mosaicism; D009043:Motor Activity; D010641:Phenotype; D065852:Spatial Memory; D016019:Survival Analysis; D000075924:X-linked Nuclear Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D007334:Insulin-Like Growth Factor I; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein
keywords: ATRX; Central nervous system; Mouse models; Neurobehaviour