FUNCTIONS AND INTERACTIONS OF CHROMOSOME 21 GENES

染色体21 q估计包含500-1000个基因， 其中一些与自身综合征的发展有关 表型此外，预计21号染色体上的许多基因 与位于基因组其他位置的基因或基因产物相互作用， 产生一系列的进一步影响。减轻 21三体需要对相关基因的了解。在这 组件，我们提出了两种方法来研究的复杂性， 唐氏综合症的基因水平(1)在现有供资下 在这个项目中，我们获得了大量的信息， 21 q基因的比例。根据这些信息，我们现在建议进一步 通过构建转基因小鼠研究几个基因。每个 选择基因是因为过度表达与 与唐氏综合症表型相关的令人信服的假设。基因 包括一种转录因子GABPA，已知它参与了 调节多种基因的表达;在RNA编辑酶中，RED 1， 已知编辑谷氨酸受体亚单位并影响其生理功能 功能;谷氨酸受体亚单位，GLuR 5;和一个假定的前mRNA 加工酶，rA 4，一个新的成员的基因家族已知影响 选择性剪接的模式过表达转基因小鼠， 基因将在分子水平上进行检查，并在 与转基因小鼠核心和小鼠行为核心的合作， 对于大体解剖学和行为表型效应， 与Davisson组件合作，用于电生理学 异常这样，我们就可以确定，如果有的话， 基因可能在神经发育和/或智力迟钝中起作用， 和唐氏综合症的认知缺陷。(2)我们将使用微分 显示以表征由以下引起的基因表达的改变： 节段性三体和单基因三体。节段性三体 将包括本发明的Ts 65 Dn和Ts 232 Dn部分16三体小鼠。 Davisson组分，以及相关的Cre/lox缺失，构建在 Berennan成分，以及小鼠10号和17号染色体区域 Cre/lox部分三体构建在布伦南组件。单个 基因转基因将包括这四个限制在这一组成部分， 一种ETS 2转基因生物已经存在。菌株将优先用于研究 基于在Brennan、Crnic、Davisson进行的表型评估， 和加德纳的核心和组件。我们将描述数字和 表达水平改变的基因的性质，并试图推断 模式和生物相关性。 这两种方法都将增加我们对神经学的理解。 发展的一般，并将定义的分子基础， 尤其是智力迟钝综合症。结果也将有助于未来 关于临床干预潜力的讨论。

Chromosome 21q is estimated to contain 500-1000 genes, and an unknown number of these are involve din the development of the own Syndrome phenotype. In addition, it is expected that many genes on chromosome 21 interact with genes or gene products located elsewhere in the genome, thus producing a cascade of further effects. Ameliorating the effects of trisomy 21 will require understanding of the genes involved. In this component, we are proposing two approaches to examine the complexity of the Down Syndrome phenotype at the gene level. (1) Under current funding of this program project, we have obtained information on a large percentage of 21q genes. From this information, we now propose further study of several genes by means of transgenic mouse construction. Each genes has been chosen because over expression is associated with a compelling hypothesis for relevance to the Down Syndrome phenotype. Genes include a transcription factor, GABPA known to be involved in the regulation of expression of a wide variety of genes; in RNA editase, RED1, known to edit glutamate receptor subunits and affect their physiological functioning; a glutamate receptor subunit, GLuR5; and a putative pre-mRNA processing enzyme, rA4, a novel member of a gene family known to affect patterns in alternative splicing. Over expressing transgenic mice for each gene will be examined at the molecular level in this component, and in collaboration with the Transgenic Mouse Core and the Mouse Behavior Core, for gross anatomical and behavioral phenotypic effects, and in collaboration with the Davisson component, for electrophysiological abnormalities. In this way, we will determine what role, if any, these genes may play in neurological development and/or the mental retardation and cognitive deficits od Down Syndrome. (2) We will use differential display to characterize the alterations in gene expression caused by segmental trisomies and trisomy of single genes. The segmental trisomies will include both the Ts65Dn and Ts232Dn partial trisomy 16 mice of the Davisson component, and associated Cre/lox deletions constructed in the Berennan component, as well as the mouse chromosome 10 and 17 region Cre/lox partial trisomies constructed in the Brennan component. Single gene transgenics will include the four constricted in this component and a ETS2 transgenic already available. Strains will be prioritized for study based on phenotypic assessments carried out in Brennan, Crnic, Davisson and Gardiner cores and components. We will characterize the number and the natures of the genes altered in expression level and attempt to deduce patterns and biological relevance. Both of these approaches will increase our understanding of neurological development in general, and will define the molecular basis of Down Syndrome mental retardation in particular. Results will also aid in future discussions relating to clinical intervention potentials.