DOWN SYNDROME NEUROGENESIS AND COGNITION--GENES AND FUNCTION

唐氏综合症（DS）是遗传性精神疾病的主要公认原因。 弱智（MR），影响30多万人的福利 仅在美国。虽然患有DS的人的大脑 出生时没有明显异常，出现小头畸形， 前额皮质和小脑蚓部，并显示出特征性 包括退化和扭曲的微妙异常， 树突树和棘，皮质层缺陷，以及 异常的突触本文所述研究的最终目标是 建议开始通过阐明这些缺陷的原因来确定这些缺陷的原因， 唐氏综合征的基因和认知之间的途径， 模型来改善它们。在过去的5年里，一个强大的阵列 包括21号染色体基因，DS 表型图和DS小鼠模型。作为确定 这些基因对神经解剖和功能至关重要， DS的缺陷，DS精神发育迟滞的一部分的一致区域， 和一个密集的连续克隆阵列 覆盖超过4 Mb的两个关键区域，一个 与MMU 16同源，另一个与MMU 10同源。我们已经分离出 来自这些区域的表征的人类和小鼠基因同源物， 在人脑中的表达。这些基因包括DS-CAM，编码一种新的 神经细胞粘附分子的一员，负责形态发生 脊椎动物大脑的功能。具体表现在 神经系统，它占据整个候选区域的10-15%，并且它 是一些微妙的结构和认知缺陷的强有力的候选人， DS; PEP 19，仅在出生后小脑中表达的肽， 视网膜; CHD 1，在胎脑和棕色脂肪中高度表达; hPWP 2，a 负责细胞分离的酵母同源物;TMEM，一种大的，普遍存在的 跨膜蛋白 我们提出四个目标：一。为了表征21号染色体基因表达， 唐氏综合征和对照组出生前后的大脑 使用Northerns，组织原位杂交和 免疫细胞化学基因将包括DS-CAM、CHD 1、hPWP 2、PEP-19和 TMEM-1。二.表征人21个同源物的小鼠基因表达 在正常的Ts 65 Dn和Cre-Lox小鼠中， 用免疫组织化学和组织原位杂交。三.到 利用表达的21号染色体基因构建转基因和敲除小鼠 在人类大脑中。四.分析Aim III中的转基因和基因敲除小鼠 一般和神经解剖学，基因表达和行为。这些模型 将提供线索，大脑形态和认知在DS和 正常的发展，并提供模型， 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.