Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice
Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice
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DOI：
10.1093/hmg/11.3.253
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发表时间：
2002-02-01
影响因子：
3.5
通讯作者：
Picketts, DJ
中科院分区：
文献类型：
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作者：
Bérubé, NG;Jagla, M;Picketts, DJ
几种X连锁精神发育迟滞综合征是由ATRX基因突变引起的。与ATRX突变相关的常见临床特征包括严重的精神发育迟滞、特征性面部异常和不同程度的泌尿生殖缺陷和α-地中海贫血。虽然ATRX蛋白是染色质重塑蛋白的SWI/SNF家族的成员，但关于ATRX蛋白的生化活性或其在发育期间的体内功能知之甚少。在这里，我们表明，ATRX是一个大的多蛋白复合物的一部分，类似于SWI/SNF复合物的大小。此外，我们已经产生了过表达ATRX的转基因小鼠作为研究这种蛋白质在发育过程中的功能的初始模型。ATRX的错误表达与生长迟缓、神经管缺陷和胚胎死亡的高发生率有关。此外，来自E10.5转基因胚胎的大脑显示出异常的生长和脑室区的组织，在受影响最严重的胚胎中，脑室区高度卷曲。存活至出生的转基因小鼠表现出高的围产期死亡率，以及癫痫发作，轻度颅面畸形和异常行为。我们的研究结果表明，ATRX剂量是至关重要的正常发展和组织的皮质，并强调我们的模型的相关性ATRX功能和疾病的发病机制的研究。
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.