Transgenic mouse in vivo library of human down syndrome critical region 1:: Association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration
Transgenic mouse in vivo library of human down syndrome critical region 1:: Association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration
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DOI：
10.1093/jnen/63.5.429
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发表时间：
2004-05-01
影响因子：
3.2
通讯作者：
Alleva, E
中科院分区：
文献类型：
--
作者：
Branchi, I;Bichler, Z;Alleva, E
唐氏综合症是导致智力低下的最常见的遗传原因，每700名活产婴儿中就有1人患有唐氏综合症。在目前的研究中，我们使用了一个转基因小鼠体内文库，该文库由4个酵母人工染色体(YAC)转基因小鼠品系组成，每个品系携带唐氏综合症临界区1(DCR-1)的不同片段，该片段与表征这种病理的脑异常有关。除了位于其他DCR-1片段上的基因外，152F7片段还含有DYRK1A基因，编码一种丝氨酸苏氨酸激酶。对这些小鼠品系的神经行为分析表明，在发育过程中，DYRK1A过表达152177只小鼠，而其他品系没有表现出学习障碍和多动。此外，152F7小鼠的大脑重量和神经元大小都有所增加。在生化水平上，我们发现DYRK1A的过度表达与转录因子FKHR的磷酸化水平和细胞周期蛋白B1的高水平相关，这在体内首次表明DYRK1A的过度表达与细胞周期蛋白的改变有关。此外，我们还发现CREB家族转录因子的磷酸化水平发生了变化。我们的发现支持DYRK1A过表达在唐氏综合征神经元异常中的作用，并表明这种病理与参与细胞周期调节的蛋白质水平改变有关。
Down syndrome is the most frequent genetic cause of mental retardation, having an incidence of I in 700 live births. In the present study we used a transgenic mouse in vivo library consisting of 4 yeast artificial chromosome (YAC) transgenic mouse lines, each bearing a different fragment of the Down syndrome critical region 1 (DCR-1), implicated in brain abnormalities characterizing this pathology. The 152F7 fragment, in addition to genes also located on the other DCR-1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing 152177 mice but not the other lines display learning impairment and hyperactivity during development. Additionally, 152F7 mice display increased brain weight and neuronal size. At a biochemical level we found DYRK1A overexpression associated with a development-dependent increase in phosphorylation of the transcription factor FKHR and with high levels of cyclin B 1, suggesting for the first time in vivo a correlation between DYRK1A overexpression and cell cycle protein alteration. In addition, we found an altered phosphorylation of transcription factors of CREB family. Our findings support a role of DYRK1A overexpression in the neuronal abnormalities seen in Down syndrome and suggest that this pathology is linked to altered levels of proteins involved in the regulation of cell cycle.