Saran Nidhi G, Pletcher Mathew T, Natale JoAnne E, Cheng Ying, Reeves Roger H
Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21210, USA.
Hum Mol Genet. 2003 Aug 15;12(16):2013-9. doi: 10.1093/hmg/ddg217.
Trisomy 21 (Down syndrome) results in cerebellar dysmorphology with direct parallels in the Ts65Dn mouse. Despite pronounced changes in morphology, cerebellar function is not markedly different. As a first test of whether those cerebellar cells that have survived to adulthood in trisomic mice are equivalent to euploid cells, we used microarrays to assess the trisomic and euploid cerebella. Trisomic and euploid transcriptomes were robustly distinguished. Changes in expression of individual genes were very subtle, but the differences in respective transcriptome phenotypes extended deeply into the set of nearly 7000 probes (genes) located throughout the genome. In contrast to deterministic models of gene action in trisomy, examination of the discriminating genes in two independent experiments suggests that the global perturbation includes a significant stochastic component. Thus, dosage imbalance of 124 genes in Ts65Dn mice alters the expression of thousands of genes to create a variable trisomic transcriptome. This global destabilization has important implications for approaches to ameliorative therapies in Down syndrome.
21三体综合征（唐氏综合征）会导致小脑形态异常，这在Ts65Dn小鼠中也有直接体现。尽管形态有明显变化，但小脑功能并无显著差异。作为对三体小鼠中存活至成年的小脑细胞是否等同于整倍体细胞的首次测试，我们使用微阵列来评估三体和整倍体小脑。三体和整倍体转录组有明显区分。单个基因表达的变化非常细微，但各自转录组表型的差异深入到整个基因组中近7000个探针（基因）的集合中。与三体中基因作用的确定性模型相反，在两个独立实验中对鉴别基因的检查表明，全局扰动包括一个显著的随机成分。因此，Ts65Dn小鼠中124个基因的剂量失衡会改变数千个基因的表达，从而产生可变的三体转录组。这种全局不稳定对唐氏综合征的改善性治疗方法具有重要意义。
