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Published online
doi:10.1083/jcb.200706083
The Journal of Cell Biology, Vol. 180, No. 2, 315-324
The Rockefeller University Press, 0021-9525 $30.00
© Ritchie et al.
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Article

Loss of ATRX leads to chromosome cohesion and congression defects



Kieran Ritchie1,2, Claudia Seah1,2, Jana Moulin1,2, Christian Isaac1,2, Frederick Dick1,2,3,4, and Nathalie G. Bérubé1,2,3

1 Department of Paediatrics and 2 Department of Biochemistry, University of Western Ontario, London, Canada N6A 4L6
3 Children's Health Research Institute, London, Canada N6C 2V5
4 London Regional Cancer Centre, London, Canada N6A 4L6

Correspondence to N.G. Bérubé: nberube{at}uwo.ca

{alpha}Thalassemia/mental retardation X linked (ATRX) is a switch/sucrose nonfermenting-type ATPase localized at pericentromeric heterochromatin in mouse and human cells. Human ATRX mutations give rise to mental retardation syndromes characterized by developmental delay, facial dysmorphisms, cognitive deficits, and microcephaly and the loss of ATRX in the mouse brain leads to reduced cortical size. We find that ATRX is required for normal mitotic progression in human cultured cells and in neuroprogenitors. Using live cell imaging, we show that the transition from prometaphase to metaphase is prolonged in ATRX-depleted cells and is accompanied by defective sister chromatid cohesion and congression at the metaphase plate. We also demonstrate that loss of ATRX in the embryonic mouse brain induces mitotic defects in neuroprogenitors in vivo with evidence of abnormal chromosome congression and segregation. These findings reveal that ATRX contributes to chromosome dynamics during mitosis and provide a possible cellular explanation for reduced cortical size and abnormal brain development associated with ATRX deficiency.

Abbreviations used in this paper: ANOVA, analysis of variance; ATRX, {alpha} thalassemia/mental retardation X linked; CdLS, Cornelia de Lange syndrome; CENP, centromere-associated protein; CREST, calcinosis, Raynaud's phenomenon, esophageal dismotility, sclerodactyly, and telangiectasia; CSD, chromoshadow domain; E, embryonic day; HG, HeLa-H2B-GFP; HP1, heterochromatin-binding protein 1; NIPBL, nipped-B–like; PCH, pericentromeric heterochromatin; Q-RT-PCR, quantitative RT-PCR.


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