DYRK TRANSGENIC MICE AS A MODEL FOR DOWN SYNDROME

描述：（改编自申请人的摘要）唐氏综合症是最 一种与智力迟钝有关的常见遗传病，约1 每800个活产婴儿。这种综合征是由21号染色体的三倍引起的 或者是其中的一部分，包括面部畸形，心脏病， 白血病、早发性阿尔茨海默病和精神疾病的发病率增加 迟钝后者与神经元数量减少有关， 降低了大脑许多区域神经元过程的复杂性。的 唐氏综合症的所有异常都可能是由 位于染色体上关键区域的几个基因的过表达 21q22.2，因此它是一个复杂的性状。然而， 综合征可归因于一个或几个基因。最近， 也被称为Dyrk，已经被映射到Down 综合征临界区。变异的小脑苍蝇的大脑数量减少 细胞，这表明突变的基因编码一种蛋白质， 神经发生哺乳动物Dyrks是双特异性蛋白激酶， 与果蝇Minibrain和酵母Yak1蛋白的广泛相似性 参与细胞分裂的激酶。注射含有基因组的YAC 包括Dyrk基因在内的序列在转基因小鼠中引起改变， 神经发生和认知障碍，这表明Dyrk参与了 与唐氏综合症有关的大脑异常 为了了解Dyrk是否在发育神经病理学中起作用， 研究人员发现， 计划首先详细分析表达和活动的正常模式， Dyrk在发育中的小鼠大脑中。第二，他们将创造转基因小鼠 其瞬时特异性地表达高水平的Dyrk， 发育中大脑的增殖区。最后，他们将分析在 详细描述这些小鼠的大脑，以确定是否减少了 神经元细胞，或其他缺陷让人想起唐氏综合症，已经发生， 这是神经发生期间大脑中Dyrk过度表达的结果。 他们的转基因小鼠可能作为一种新的动物模型，研究 唐氏综合征智力低下的分子基础

DESCRIPTION: (adapted from applicant's abstract) Down Syndrome is the most common genetic disease associated with mental retardation, affecting about 1 in every 800 live births. The syndrome results from triplication of chromosome 21 or a segment of it, and it includes facial abnormalities, heart disease, increased frequency of leukemia, early-onset Alzheimer's disease and mental retardation. The latter is associated with decreased neuronal number and reduced complexity of neuronal processes in many regions of the brain. The entire spectrum of Down Syndrome abnormalities likely results from overexpression of several genes located in a critical region on chromosome 21q22.2, and it is thus a complex trait. However, individual aspects of the syndrome may be attributable to one or few genes. Recently, the human homologue of Drosophila minibrain, also known as Dyrk, has been mapped to the Down Syndrome critical region. Mutant minibrain flies have a reduced number of brain cells, suggesting that the mutated gene encodes a protein involved in neurogenesis. Mammalian Dyrks are dual specificity protein kinases with extensinve similarities to Drosophila Minibrain and to the yeast Yak1 protein kinase involved in cell division. Injection of a YAC containing genomic sequences including the Dyrk gene in transgenic mice causes altered neurogenesis and cognitive impairment, suggesting that Dyrk is involved in the brain abnormalities associated with Down Syndrome. To understand whether Dyrk plays a role in the developmental neuropathology underlying the mental retardation aspect of Down Syndrome, the investigators plan to first analyze in detail the normal pattern of expressionand activity of Dyrk in the developing mouse brain. Second, they will create transgenic mice that transiently and specifically express elevated levels of Dyrk in the proliferative zone of the developing brain. Finally, they will analyze in detail the brains of these mice to ascertain whether reduction in the number of neuronal cells, or other defects reminiscent of Down Syndrome, have occurred as a result of Dyrk overexpression in the brain during the period of neurogenesis. Their transgenic mice may serve as a novel animal model to investigate the molecular basis of mental retardation in Down Syndrome.