MOUSE MODELS OF DOWN SYNDROME: PHENOTYPIC MAPPING

这项研究计划的总体目标是发现 多出一份人类染色体的机制 21产生唐氏综合征（DS）的表型。 我们的方法 使用的前提是， 三体表型的特定组分增加 存在于21号染色体上的基因或基因组的表达。 我们的工作 在这个问题上，已经导致了几种动物模型的发展， DS包括完全的16三体（Ts 16）小鼠，最近， 新的部分16三体小鼠Ts 1Cje和Ms 1 Ts 65，它们是来自 分别从低于Sod 1到Mx和从高于App到高于Sod 1。在 此外，我们还研究了另一种部分16三体小鼠Ts 65 Dn， 对于区域App至Mx是三体的。 Ts 1Cje异常 和Ts 65 Dn，它们更忠实地再现了遗传不平衡， 结果比Ts 16，主要限于神经 系统和影响学习和行为，虽然Ts 65 Dn也是男性 不育。Ts 65 Dn的失衡程度越大，其异常程度越高 (in Ts 108 Cje的空间学习能力。 此外，Ts 65 Dn小鼠 显示基底前脑胆碱能神经元（BFCN）萎缩， 可以被神经生长因子逆转，但Ts 108 Cje动物具有正常的 BFCN。 为了确定染色体上负责 部分三体小鼠的学习障碍和神经元萎缩 对于DS，我们将首先详细比较行为差异 在Ts 1Cje、Ts 65 Dn和Ms 1 Ts 65中。 然后，我们将使用一种方法， 本质上是减法的表型作图。 它是基于 分析表型的变化，这是由于减少了 三体性区域中特定基因座的大小或去除。 我们 应分析删除App或Sod 1对 Ts 65 Dn的表型。 然后，从Ts 65 Dn和Ts 108 Cje开始，我们将 用进行性辐射产生两个系列的部分Ts 16小鼠- 导致16号染色体缺失 由此产生的后代将是 评估部分Ts 16的表型特征 当染色体特定区域的额外拷贝消失时， 不再存在。然后可以进一步分析如此确定的区域 以确定候选基因，以及这些基因在 产生部分16三体的表型变化， 通过转基因和同源重组技术建立。

The overall objective of this research program is to discover the mechanisms by which the presence of an extra copy of human chromosome 21 produces the phenotype of Down syndrome (DS). The approach we are using is based on the premise that it will be possible to relate specific components of the trisomic phenotype to the increased expression of genes or sets of genes present on chromosome 21. Our work on this problem has led to the development of several animal models for DS including the full trisomy 16 (Ts16) mouse and, very recently, the new partial trisomy 16 mice, Ts1Cje and Ms1Ts65, which are trisomic from below Sod1 to Mx and from above App to above Sod1, respectively. In addition, we have studied Ts65Dn, another partial trisomy 16 mouse which is trisomic for the region App to Mx. The abnormalities of the Ts1Cje and Ts65Dn, which more faithfully reproduce the genetic imbalance that results in DS than does Ts16, are principally restricted to the nervous system and affect learning and behavior, although Ts65Dn is also male sterile. Ts65Dn, with the larger degree of imbalance, is more abnormal (in spatial learning) than is Ts108Cje. Furthermore, Ts65Dn mice display atrophy of basal forebrain cholinergic neurons (BFCN) which can be reversed by nerve growth factor, but Ts108Cje animals have normal BFCN. To determine the regions of chromosome that are responsible for the learning deficits and neuronal atrophy in the partial trisomy mouse for DS, we shall first compare in detail the behavioral differences among Ts1Cje, Ts65Dn, and Ms1Ts65. We shall then use an approach to phenotypic mapping that is subtractive in nature. It is based on the analysis of the changes in phenotype that result from decreases in the size of or the removal of specific loci from the region of trisomy. We shall analyze the effects of deleting either App or Sod1 on the phenotype of Ts65Dn. Then, starting with Ts65Dn and Ts108Cje, we shall generate two series of partial Ts16 mice with progressive radiation- induced deletions of chromosome 16. The resulting progeny will be assessed with regard to which phenotypic features of partial Ts16 disappear as extra copies of particular regions of the chromosome are no longer present. Regions so identified can then be further analyzed to identify candidate genes, and the true role of these genes in producing the phenotypic changes of partial trisomy 16 can be established by transgenic and homologous recombination techniques.