DOWN SYNDROME NEUROGENESIS AND COGNITION--GENES AND FUNCTION

唐氏综合征(DS)是公认的遗传性精神疾病的主要原因 智力迟缓(MR)，影响30多万人的福利 仅在美国。DS患者的大脑，尽管 出生时并不严重异常，发展为小头畸形，大小减少 前额叶皮质和小脑虫，并表现出特征性 微妙的异常，包括倒退和扭曲的 树突状突起和棘突，皮质分层有缺陷，以及 异常突触。本文件中描述的研究的最终目标 建议开始通过澄清来确定这些缺陷的原因 唐氏综合征患者的基因与认知通路 用来改进它们的模型。在过去的5年里，一个强大的阵列 已经开发出包括21号染色体基因的DS 表型图和DS的小鼠模型。作为标识 对神经解剖和功能至关重要的基因子集 DS缺陷是部分DS精神发育迟滞的共同区域 由该组件生成，以及密集的连续克隆数组 构建了覆盖超过4Mb的两个临界区，一个 与MMU16同源，另一个与MMU10同源。我们已经隔离了 描述了来自这些区域的人和鼠的基因同源物 在人脑中表达。这些基因包括DS-CAM，编码一种新的 神经细胞黏附分子的成员，负责形态发生 以及脊椎动物大脑的功能。具体表达在 神经系统，它占据了整个候选区域的10%-15%，而且它 是一些细微的结构和认知缺陷的有力候选者 DS；PEP19，一种仅在出生后小脑表达的多肽，以及 视网膜；CHD1，在胎脑和棕色脂肪中高表达；hPWP2，a 酵母同系物负责细胞分离；TMEM，一种大型的，无处不在的 跨膜蛋白。 我们提出了四个目标：1.研究21号染色体基因的表达 唐氏综合征患者及对照组出生前后的脑功能研究 利用Northerns、组织原位杂交和 免疫细胞化学。基因将包括ds-CAM、CHD1、hPWP2、PEP-19和 TMEM-1。II.人类21个同源物的小鼠基因表达特征 在具有适当复制的正常、Ts65Dn和Cre-Lox小鼠中， 采用免疫组织化学和组织原位杂交方法。三、至 利用表达的21号染色体基因构建转基因和敲除小鼠 在人脑中。在AIM III中分析转基因和基因敲除小鼠 用于一般和神经解剖学、基因表达和行为。这些型号 将为DS和IN患者的脑形态发生和认知提供线索 正常开发，并提供用于测试的模型 治疗策略。

Down Syndrome (DS) is the major recognized cause of genetic mental retardation (MR) and affects the welfare of more than 300,000 individuals in the United States Alone. The brains of individuals with DS, although not grossly abnormal at birth, develop microcephaly with decreased size of the prefrontal cortex and cerebellar vermis, and show characteristic subtle abnormalities that include regression and distortion of the dendritic tree and spines, defective lamination of the cortex, and abnormal synapses. The ultimate goal of the research described in this proposal is to began to define the cause of these defects by elucidating the pathways between genes and cognition in Down syndrome and providing models in which to ameliorate them. In the past 5 years, a powerful arrays of tolls has been developed including chromosome 21 genes, the DS phenotypic map, and mouse models of DS. As a first step in identifying a subset of genes that are critical for the neuroanatomic and functional defects of DS, a consensus region for a part of DS mental retardation was generated by this component, and a dense contiguous array of clones covering more than 4 Mb of two critical regions was constructed, one homologous to MMU16 and the other to MMU10. We have isolated and characterized human and mouse gene homologs from these regions that are expressed in the human brain. These genes include DS-CAM, encoding a novel member of neural cell adhesion molecules, responsible for morphogenesis and function of the vertebrate brain. Expressed specifically in the nervous system, it occupies 10-15% of the entire candidate region, and it is a strong candidate for some subtle structural and cognitive defects of DS; PEP19, a peptide expressed only in the post-natal cerebellum and retina; CHD1, highly expressed in fetal brain and brown fat; hPWP2, a yeast homolog responsible for cell separation;TMEM, a large, ubiquitous transmembrane protein. We propose four aims: I. To characterize chromosome 21 gene expression in the brains of Down syndrome and controls during pre and post-natal development using Northerns, tissue in situ hybridization and immunocytochemistry. Genes will include DS-CAM, CHD1, hPWP2, PEP-19 and TMEM-1. II. To characterize mouse gene expression of human 21 homologues in normal, Ts65Dn and Cre-Lox mice with the appropriate duplications, using immunohistochemistry and tissue in situ hybridization. III. To construct transgenic and knockout mice using chromosome 21 genes expressed in the human brain. IV. To analyze transgenic and knockout mice in Aim III for general and neuroanatomy, gene expression and behavior. These models will provide clues to brain morphogenesis and cognition in DS and in normal developments as well as providing models in which to test strategies for treatment.