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Dis Model Mech. 2017 Feb 1;10(2):119-126. doi: 10.1242/dmm.027482. Epub 2017 Jan 12.

Mosaic expression of Atrx in the mouse central nervous system causes memory deficits.

Author information

1
Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada.
2
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.
3
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, Ontario N6A 3K7, Canada.
4
Department of Anatomy and Cell Biology and Robarts Research Institute, the University of Western Ontario, London, Ontario N6A 3K7, Canada.
5
Division of Genetics and Development, Children's Health Research Institute, London, Ontario N6C 2V5, Canada nberube@uwo.ca.

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.

KEYWORDS:

ATRX; Central nervous system; Mouse models; Neurobehaviour

PMID:
28093507
PMCID:
PMC5312007
DOI:
10.1242/dmm.027482
[Indexed for MEDLINE]
Free PMC Article

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