Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome
Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome
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DOI：
10.1093/hmg/10.18.1915
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发表时间：
2001-09-01
影响因子：
3.5
通讯作者：
Estivill, X
中科院分区：
文献类型：
--
作者：
Altafaj, X;Dierssen, M;Estivill, X
唐氏综合征（Down's syndrome，DS）是导致智力低下、肌张力减退和发育迟缓的主要原因。携带大型鼠或人基因组片段的DS小鼠模型显示运动改变和记忆缺陷。负责这些表型改变的特定基因尚未确定。DYRK 1A是果蝇minibrain基因的人类同源物，定位于人类21号染色体的DS关键区域，并在DS胎儿脑中过表达。DYRK 1A编码丝氨酸-苏氨酸激酶，可能参与成神经细胞增殖。突变的果蝇小脑果蝇的视叶和中枢都减少了，表现出学习缺陷和活动减退。我们已经产生过表达Dyrk 1A全长cDNA的转基因小鼠（TgDyrk 1A）。TgDyrk 1A小鼠表现出延迟的头尾成熟与神经运动发育的功能后果。TgDyrk 1A小鼠也表现出改变的运动技能获得和多动，并维持到成年。在Morris水迷宫中，TgDyrk 1A小鼠在空间学习和认知灵活性方面表现出显著的损伤，表明海马和前额皮质功能障碍。在更复杂的重复逆转学习范式中，这种缺陷被证明与参考记忆有关，而工作记忆几乎没有受损。这些变化与部分三体染色体16小鼠模型中发现的DS和提示的病因作用DYRK 1A在精神发育迟滞和运动异常的DS。
Down's syndrome (DS) is a major cause of mental retardation, hypotonia and delayed development. Murine models of DS carrying large murine or human genomic fragments show motor alterations and memory deficits. The specific genes responsible for these phenotypic alterations have not yet been defined. DYRK1A, the human homolog of the Drosophila minibrain gene, maps to the DS critical region of human chromosome 21 and is overexpressed in DS fetal brain. DYRK1A encodes a serine-threonine kinase, probably involved in neuroblast proliferation. Mutant Drosophila minibrain flies have a reduction in both optic lobes and central brain, showing learning deficits and hypoactivity. We have generated transgenic mice (TgDyrk1A) overexpressing the full-length cDNA of Dyrk1A. TgDyrk1A mice exhibit delayed craniocaudal maturation with functional consequences in neuromotor development. TgDyrk1A mice also show altered motor skill acquisition and hyperactivity, which is maintained to adulthood. In the Morris water maze, TgDyrk1A mice show a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect turned out to be specifically related to reference memory, whereas working memory was almost unimpaired. These alterations are comparable with those found in the partial trisomy chromosome 16 murine models of DS and suggest a causative role of DYRK1A in mental retardation and in motor anomalies of DS.