The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.
The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.
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DOI：
10.1002/ajmg.a.37156
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Bianchi DW
中科院分区：
文献类型：
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作者：
Guedj F;Pennings JL;Ferres MA;Graham LC;Wick HC;Miczek KA;Slonim DK;Bianchi DW
患有唐氏综合症的人类胎儿表现出大脑发育异常和神经再生减少。尽管这种表型在产前发病，但大多数治疗试验都是在成年人身上进行的。在这里，我们提出了唐氏综合症Ts1Cje小鼠模型中胎儿大脑分子和新生儿行为改变的证据。胚胎15.5天Ts1Cje胚胎(n=5)和野生型产仔鼠(n=5)的大脑半球RNA处理后与小鼠基因1.0 ST阵列杂交。生物信息学分析用于确定Ts1Cje胎脑发育过程中的差异基因和调控途径。在单独的实验中，分别使用Fox量表、超声波发声和归巢测试来调查Ts1Cje幼崽(n=29)和WT窝仔(n=)在出生后3-21天的行为缺陷。与年龄匹配的整倍体大脑相比，Ts1Cje胎儿大脑(n=71)显示出比成人(n=31)更多的差异调控基因。Ts1Cje胚胎脑细胞周期标志物表达上调，溶质载体氨基酸转运体表达下调。几个细胞过程在这两个阶段都是失调的，包括细胞凋亡、炎症、JAK/STAT信号、G蛋白信号和氧化还原酶活性。此外，还观察到早期行为缺陷，如表面翻正、厌恶悬崖、负向趋地性、前肢抓握、超声波发声和归巢试验。Ts1Cje小鼠模型在胎脑发育过程中表现出基因表达异常，在断奶前阶段表现出明显的新生儿行为缺陷。结合人类研究，这表明唐氏综合征的表型在产前就表现出来，并为产前治疗改善围产期大脑发育和产后神经认知提供了理论基础。
Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3–21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and post-natal neurocognition.