MOUSE MODELS OF DOWN SYNDROME: PHENOTYPIC MAPPING

这项研究计划的总体目标是发现 人类染色体多一个拷贝存在的机制 21产生唐氏综合征(DS)的表型。我们正在采取的方法 使用是建立在这样的前提下的，即它将可能与 三体表型的特定成分增加 21号染色体上存在的基因或基因组的表达。我们的工作 关于这个问题已经导致了几个动物模型的发展 DS包括完整的16三体(TS16)小鼠，最近， 新的部分三体16小鼠，Ts1Cje和Ms1Ts65，它们是来自 分别在SOd1以下至Mx和从App上方至SOd1上方。在……里面 此外，我们还研究了另一种部分16三体小鼠Ts65Dn 区域App-Mx是三体的。Ts1Cje的异常 和Ts65Dn，它们更真实地再现了 与TS16相比，DS的结果主要局限于神经 系统和影响学习和行为，尽管Ts65Dn也是男性 无菌的。Ts65Dn的不平衡程度越大，越不正常 (在空间学习方面)Ts108Cje。此外，Ts65Dn小鼠 基底前脑胆碱能神经元(BFCN)萎缩 被神经生长因子逆转，但Ts108Cje动物正常 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它们的行为差异 在Ts1Cje、Ts65Dn和Ms1Ts65中。然后，我们将使用一种方法来 本质上是减法的表型作图。它是基于 表型变化的分析，这些表型变化是由于 三体区域的大小或从三体区域移除特定的基因。我们 应分析删除App或SOD1对 Ts65Dn的表型。然后，从Ts65Dn和Ts108Cje开始，我们将 产生两个系列的部分TS16小鼠进行渐进辐射- 导致16号染色体的缺失。由此产生的后代将是 根据部分TS16的哪些表型特征进行评估 随着染色体特定区域的额外复制而消失 不再存在。然后，可以进一步分析这样确定的区域 以确定候选基因，以及这些基因在 产生部分三体16的表型变化可能是 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.