Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome
Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome
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DOI：
10.1093/hmg/10.11.1163
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发表时间：
2001-05-15
影响因子：
3.5
通讯作者：
Oshimura, M
中科院分区：
文献类型：
--
作者：
Shinohara, T;Tomizuka, K;Oshimura, M
21三体（Ts 21）是最常见的活产人类非整倍体;它导致一系列被称为唐氏综合征（DS）的特征，Ts 21是先天性心脏缺陷的最常见原因，也是智力迟钝的主要遗传原因。为了研究额外拷贝的人21号染色体（Chr 21）对不同表型的基因剂量效应，我们利用微细胞介导的染色体转移技术建立了含有Chr 21的胚胎干细胞，并利用保留Chr 21作为独立染色体的ES细胞系制备了含有大量Chr 21细胞的嵌合小鼠。荧光原位杂交和基于PCR的DNA分析显示，Chr 21是substationally完整的，但持续了一个小的缺失。自由分离的Chr 21在发育过程中在某些组织中丢失，导致一组嵌合小鼠具有关于Chr 21保留的各种嵌合现象。这些嵌合小鼠通过旷场、情境恐惧条件反射和强迫游泳测试显示，Chr 21在脑中的保留与学习或情绪行为的损害之间存在高度相关性。胸腺发育不良和心脏缺陷，即双出口右心室和骑式主动脉，在相当数量的嵌合体小鼠胎儿中观察到高贡献的Chr 21。这些嵌合小鼠模仿了各种各样的DS表型性状，揭示了含有Chr 21的小鼠作为DS的独特模型和用于鉴定负责DS的基因的实用性。
Trisomy 21 (Ts21) is the most common live-born human aneuploidy; it results in a constellation of features known as Down's syndrome (DS), Ts21 is the most frequent cause of congenital heart defects and the leading genetic cause of mental retardation. To investigate the gene dosage effects of an extra copy of human chromosome 21 (Chr 21) on various phenotypes, we used microcell-mediated chromosome transfer to create embryonic stem (ES) cells containing Chr 21, ES cell lines retaining Chr 21 as an independent chromosome were used to produce chimeric mice with a substantial contribution from Chr 21-containing cells. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that Chr 21 was substationally intact but had sustained a small deletion. The freely segregating Chr 21 was lost during development in some tissues, resulting in a panel of chimeric mice with various mosaicism as regards retention of the Chr 21, These chimeric mice showed a high correlation between retention of Chr 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning and forced swim tests. Hypoplastic thymus and cardiac defects, i.e. double outlet right ventricle and riding aorta, were observed in a considerable number of chimeric mouse fetuses with a high contribution of Chr 21. These chimeric mice mimic a wide variety of phenotypic traits of DS, revealing the utility of mice containing Chr 21 as unique models for DS and for the identification of genes responsible for DS.