Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks.
Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks.
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DOI：
10.1186/1471-2164-15-624
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发表时间：
2014-07-22
期刊：
影响因子：
4.4
通讯作者：
Scott HS
中科院分区：
文献类型：
--
作者：
Ling KH;Hewitt CA;Tan KL;Cheah PS;Vidyadaran S;Lai MI;Lee HC;Simpson K;Hyde L;Pritchard MA;Smyth GK;Thomas T;Scott HS
唐氏综合征(DS)的Ts1Cje小鼠模型具有小鼠16号染色体(MMU16)的部分三倍体，该染色体与人类21号染色体部分同源。这些小鼠出现了在DS患者中发现的各种神经病理特征。我们分析了部分复制MMU16片段对Ts1Cje小鼠出生后1天、15天、30天和84天四个时间点大脑皮层、小脑和海马区整体基因表达的影响。基因表达谱鉴定了Ts1Cje和二体小鼠之间的总共317个差异表达基因(Deg)，这些基因是从各种时空比较中挑选出来的。总共从小脑鉴定出201个DEG，从海马体鉴定出129个DEG，从大脑皮层鉴定出40个DEG。其中，只有18个deg被鉴定为所有三个脑区共有的，15个位于三重节段。我们验证了来自大脑皮层的8个DEG(Brwd1，Donson，Erdr1，Ifnar1，Itgb8，ItsN1，MRps6和Tem50b)，来自小脑的18个Deg(Atp50，Brwd1，Donson，Depey2，Erdr1，HMGN1，Ifnar1，Ifnar2，Ifngr2，Itgb8，Itsn1，MRPS6，Paxbp1，Son，STAT1，Tbata，Tem50b和WRb)和11个来自海马体的Deg(Atp5o，Brwd1，Cbr1，Donson，Erdr1，Itgb8，Itsn1，Morc3，Son，Temb50b和WRb)。对317个DEG的功能聚类分析发现，干扰素相关的信号转导是Ts1Cje出生后脑发育最显著的失调途径。RT-qPCR和Western blotting分析表明，与野生型相比，Ifnar1和STAT1在P84Ts1Cje大脑皮层和小脑中均有高表达。这些结果提示，干扰素受体的过度表达可能导致Jak-Stat信号通路的过度刺激，这可能是Ts1Cje或DS脑的神经病理机制之一。干扰素介导的信号转导途径包括Jak-Stat信号通路的激活或抑制在包括DS在内的各种生物学过程和疾病模型中都有很好的特征，但关于该通路在Ts1Cje或DS脑的发育和功能中的作用的信息仍然很少，值得进一步研究。本文的在线版本(DOI：10.1186/1471-2164-15-624)包含补充材料，授权用户可以使用。
The Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84. Gene expression profiling identified a total of 317 differentially expressed genes (DEGs), selected from various spatiotemporal comparisons, between Ts1Cje and disomic mice. A total of 201 DEGs were identified from the cerebellum, 129 from the hippocampus and 40 from the cerebral cortex. Of these, only 18 DEGs were identified as common to all three brain regions and 15 were located in the triplicated segment. We validated 8 selected DEGs from the cerebral cortex (Brwd1, Donson, Erdr1, Ifnar1, Itgb8, Itsn1, Mrps6 and Tmem50b), 18 DEGs from the cerebellum (Atp5o, Brwd1, Donson, Dopey2, Erdr1, Hmgn1, Ifnar1, Ifnar2, Ifngr2, Itgb8, Itsn1, Mrps6, Paxbp1, Son, Stat1, Tbata, Tmem50b and Wrb) and 11 DEGs from the hippocampus (Atp5o, Brwd1, Cbr1, Donson, Erdr1, Itgb8, Itsn1, Morc3, Son, Tmem50b and Wrb). Functional clustering analysis of the 317 DEGs identified interferon-related signal transduction as the most significantly dysregulated pathway in Ts1Cje postnatal brain development. RT-qPCR and western blotting analysis showed both Ifnar1 and Stat1 were over-expressed in P84 Ts1Cje cerebral cortex and cerebellum as compared to wild type littermates. These findings suggest over-expression of interferon receptor may lead to over-stimulation of Jak-Stat signaling pathway which may contribute to the neuropathology in Ts1Cje or DS brain. The role of interferon mediated activation or inhibition of signal transduction including Jak-Stat signaling pathway has been well characterized in various biological processes and disease models including DS but information pertaining to the role of this pathway in the development and function of the Ts1Cje or DS brain remains scarce and warrants further investigation. The online version of this article (doi:10.1186/1471-2164-15-624) contains supplementary material, which is available to authorized users.
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