Kiss J, Schlumpf M, Balázs R
Collaborative Centre, National Institute for Medical Research, London, U.K.
Brain Res Dev Brain Res. 1989 Dec 1;50(2):251-64. doi: 10.1016/0165-3806(89)90201-0.
Brain development, examined at embryonic day 17, was retarded in murine trisomy 16 (Ts16). Ts16 is considered to serve as a model of the human trisomy 21 (Down's syndrome) by virtue of the presence in the mouse chromosome 16 of a set of genes located in humans in the segment of chromosome 21 that is requisite to produce the phenotypic features of Down's syndrome when present in triplicate. In addition to a reduction in brain size and cortical thickness, we observed a severe reduction throughout the brain in the density of muscarinic receptors, assessed by autoradiographic detection of specifically bound tritiated N-methyl-scopolamine, and by the failure of the development of the differentiated pattern of receptor distribution in the brainstem. The effect of gene dosage was also examined on specific neuronal populations. The distribution of acetylcholine esterase (AChE)-, tyrosine hydroxylase (TH)- and 5-hydroxytryptamine (5-HT)-positive cells in the trisomic brain was similar to that observed in chromosomally balanced littermates. On the other hand, the number of AChE-positive cells was 60-70% of the estimates in littermate controls in regions containing the septum, the vertical and horizontal limbs of the diagonal band and the basal forebrain cholinergic nuclei. Similarly, the number of TH-positive cells was reduced by about 30% in the pons. In contrast, in the trisomic foetuses the number of TH-positive cells in the mesencephalon and the diencephalon was similar to that in littermate controls, while that of 5-HT-positive cells in the mesencephalic nuclei was only slightly affected, if at all. Ts16 results, therefore, in a selective retardation of some neuronal systems, and this may lead to a perturbation of brain development. Furthermore, the systems whose development was retarded selectively are those which in Down's syndrome adults exhibit pronounced deficits of cells that--in case the murine Ts16 is a valid model--may also involve developmental disorders.
在胚胎第17天对大脑发育进行检查时，发现小鼠16三体（Ts16）存在大脑发育迟缓的情况。由于小鼠16号染色体上存在一组基因，这些基因在人类中位于21号染色体片段上，当该片段以三倍体形式存在时会产生唐氏综合征的表型特征，所以Ts16被认为可作为人类21三体（唐氏综合征）的模型。除了脑体积减小和皮质厚度变薄外，我们还观察到整个大脑中毒蕈碱受体密度严重降低，这是通过放射自显影检测特异性结合的氚标记N-甲基东莨菪碱来评估的，并且脑干中受体分布的分化模式未能发育。还研究了基因剂量对特定神经元群体的影响。在三体大脑中，乙酰胆碱酯酶（AChE）、酪氨酸羟化酶（TH）和5-羟色胺（5-HT）阳性细胞的分布与染色体平衡的同窝仔鼠中观察到的分布相似。另一方面，在含有隔区、斜角带垂直和水平支以及基底前脑胆碱能核的区域中，AChE阳性细胞的数量是同窝对照估计值的60 - 70%。同样，脑桥中TH阳性细胞的数量减少了约30%。相比之下，在三体胎儿中，中脑和间脑中TH阳性细胞的数量与同窝对照相似，而中脑核中5-HT阳性细胞的数量即使受到影响也只是轻微的。因此，Ts16导致一些神经元系统选择性发育迟缓，这可能会导致大脑发育紊乱。此外，那些发育被选择性迟缓的系统，在唐氏综合征成年人中表现出明显的细胞缺陷，而如果小鼠Ts16是一个有效的模型，这些细胞缺陷可能也涉及发育障碍。
