Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance
Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance
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DOI：
10.1038/cr.2008.305
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发表时间：
2009-02-01
期刊：
影响因子：
44.1
通讯作者：
Oshimura, Mitsuo
中科院分区：
文献类型：
--
作者：
Kai, Yoshiteru;Wang, Chi Chiu;Oshimura, Mitsuo
虽然特定的染色体综合征在表型和临床上是不同的，但大多数常染色体不平衡的个体，如非整倍体，表现为精神发育迟滞。唐氏综合征（Down syndrome，DS）是一种常见的异常表型，是最常见的常染色体非整倍体，表现为脑内神经元数量和密度的减少。作为DS模型，我们最近从含有单个人类21号染色体的ES细胞中创建了嵌合小鼠。小鼠模仿了DS的特征性表型特征，ES细胞在体外早期神经元分化过程中表现出较高的凋亡发生率。在这项研究中，我们研究了诱导异常早期神经发育的非整倍体小鼠ES细胞通过转移各种人类染色体或额外的小鼠染色体。结果表明，在体外早期神经元分化过程中，所有常染色体非整倍体克隆的凋亡发生率升高。此外，cDNA微阵列分析揭示了一个共同的下调基因簇，其中8个已知的基因与细胞增殖，轴突生长和分化。重要的是，在正常小鼠ES细胞中通过siRNA敲低靶向这些基因导致早期神经元分化期间细胞凋亡增强。这些发现有力地表明，常染色体不平衡与一般神经元的损失，通过一个共同的分子机制凋亡。
Although particular chromosomal syndromes are phenotypically and clinically distinct, the majority of individuals with autosomal imbalance, such as aneuploidy, manifest mental retardation. A common abnormal phenotype of Down syndrome (DS), the most prevalent autosomal aneuploidy, shows a reduction in both the number and the density of neurons in the brain. As a DS model, we have recently created chimeric mice from ES cells containing a single human chromosome 21. The mice mimicked the characteristic phenotypic features of DS, and ES cells showed a higher incidence of apoptosis during early neuronal differentiation in vitro. In this study, we examined the induction of anomalous early neural development by aneuploidy in mouse ES cells by transferring various human chromosomes or additional mouse chromosomes. Results showed an elevated incidence of apoptosis in all autosome-aneuploid clones examined during early neuronal differentiation in vitro. Further, cDNA microarray analysis revealed a common cluster of down-regulated genes, of which eight known genes are related to cell proliferation, neurite outgrowth and differentiation. Importantly, targeting of these genes by siRNA knockdown in normal mouse ES cells led to enhanced apoptosis during early neuronal differentiation. These findings strongly suggest that autosomal imbalance is associated with general neuronal loss through a common molecular mechanism for apoptosis.