Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice

被引:51
作者
Bérubé, NG
Jagla, M
Smeenk, C
De Repentigny, Y
Kothary, R
Picketts, DJ
机构
[1] Ottawa Hlth Res Inst, Ottawa, ON K1H 8L6, Canada
[2] Univ Ottawa, Ctr Neuromuscular Dis, Ottawa, ON, Canada
[3] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada
[4] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada
关键词
D O I
10.1093/hmg/11.3.253
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several X-linked mental retardation syndromes are caused by mutations in the ATRX gene. Common clinical features associated with ATRX mutations include severe mental retardation, characteristic facial anomalies and variable degrees of urogenital defects and alpha-thalassemia. Although the ATRX protein is a member of the SWI/SNF family of chromatin remodeling proteins, little is known about the biochemical activity of the ATRX protein or its in vivo function during development. Here we demonstrate that ATRX is part of a large multiprotein complex similar in size to the SWI/SNF complex. Furthermore, we have generated transgenic mice that overexpress ATRX as an initial model for studying the function of this protein during development. Misexpression of ATRX was associated with growth retardation, neural tube defects and a high incidence of embryonic death. Moreover, brains from E10.5 transgenic embryos displayed abnormal growth and organization of the ventricular zone that was highly convoluted in the most severely affected embryos. Transgenic mice that survived to birth exhibited a high incidence of perinatal death, as well as seizures, mild craniofacial anomalies and abnormal behavior. Our findings indicate that ATRX dosage is crucial for normal development and organization of the cortex, and emphasize the relevance of our model for the study of ATRX function and disease pathogenesis.
引用
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页码:253 / 261
页数:9
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