Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.
Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.
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DOI：
10.1242/dmm.031013
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发表时间：
2018-06-12
影响因子：
4.3
通讯作者：
Bianchi DW
中科院分区：
文献类型：
--
作者：
Aziz NM;Guedj F;Pennings JLA;Olmos-Serrano JL;Siegel A;Haydar TF;Bianchi DW
唐氏综合征（DS）是由人类21号染色体三倍化引起的。DS的神经病理学特征包括非典型中枢神经系统发育，其在产前表现并贯穿整个生命。因此，DS患者表现出认知和运动缺陷，并且在实现发育里程碑方面出现延迟。为了确定不同的DS小鼠模型是否重现了人类产前和产后表型，我们直接比较了三种细胞遗传学不同的DS小鼠模型Ts 1Cje、Ts 65 Dn和Dp（16）1/Yey在寿命期间的脑组织发生、基因表达和行为。组织学数据表明，Ts 65 Dn小鼠的躯体生长，神经发生和脑形态发生方面的影响最为一致。胚胎和成年基因表达结果显示，与Dp（16）1/Yey小鼠相比，Ts 1 Cje和Ts 65 Dn大脑中的差异表达（DEX）基因要多得多，尽管后者模型中的三重基因数量更多。此外，DEX基因在三种模型中的身份和染色体分布几乎没有重叠，导致受影响的功能途径不同。围产期和成人行为测试也突出了模型在实现各种发育里程碑和执行基于海马和运动任务的能力方面的差异。有趣的是，Dp（16）1/Yey小鼠在产前大脑表型中没有显示出异常，但它们在出生后第15天开始表现出行为缺陷，并持续到成年。相比之下，Ts 1Cje小鼠表现出轻度异常的胚胎脑表型，但只有选择行为缺陷的新生儿和成年人。总而言之，我们的数据显示了这三种小鼠模型之间在行为，基因表达和大脑发育表型方面的广泛和意想不到的根本差异。我们的研究结果说明了在研究DS的大脑发育和功能方面时，每个模型的独特局限性。这项工作有助于在未来的研究中为模型选择提供信息，研究观察到的神经发育异常如何出现，它们如何导致认知障碍，以及何时测试治疗分子以改善与DS相关的智力障碍。.编辑的选择：唐氏综合征的三种小鼠模型中的皮质生成、基因表达和行为的比较揭示了模型之间的主要差异以及每个品系在理解人类表型的神经生物学变化方面的显著局限性。
Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits, and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here, we directly compared brain histogenesis, gene expression and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared with Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS. . Editor's choice: Comparison of corticogenesis, gene expression and behavior in three mouse models of Down syndrome revealed major differences between the models as well as significant limitations in each strain for understanding neurobiological changes in the human phenotype.
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影响因子：
2
作者：
de Graaf, Gert;Buckley, Frank;Skotko, Brian G.
通讯作者：
Skotko, Brian G.
影响因子：
5.3
作者：
Chakrabarti, Lina;Galdzicki, Zygmunt;Haydar, Tarik F.
通讯作者：
Haydar, Tarik F.
识别TS65DN和TS1CJE鼠标线中的易位断点：与唐氏综合症建模的相关性。
影响因子：
2.5
作者：
Duchon, Arnaud;Raveau, Matthieu;Chevalier, Claire;Nalesso, Valerie;Sharp, Andrew J.;Herault, Yann
通讯作者：
Herault, Yann
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.3
作者：
Das, Ishita;Reeves, Roger H.
通讯作者：
Reeves, Roger H.