Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse
Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse
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DOI：
10.1093/hmg/9.2.195
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发表时间：
2000-01-22
影响因子：
3.5
通讯作者：
Reeves, RH
中科院分区：
文献类型：
--
作者：
Baxter, LL;Moran, TH;Reeves, RH
唐氏综合症（DS）是智力低下最常见的遗传原因，影响大脑发育的许多方面。 DS个体表现出大脑整体尺寸减小，小脑体积减小得不成比例。 Ts65Dn 小鼠在小鼠 16 号染色体远端 12-15 Mb 处呈节段三体性，该区域与人类 21 号染色体显示出完美的保守连锁，因此为 DS 提供了遗传模型。在这项研究中，高分辨率磁共振成像和组织学分析证明了 DS 和 Ts65Dn 小脑之间精确的神经解剖学相似性。由于小脑内部颗粒层和分子层的减少，Ts65Dn 小鼠的小脑体积显着减少，内部颗粒层细胞密度的减少进一步减少了颗粒细胞数量。尽管 Ts65Dn 小脑结构发生了这些变化，但在多项测试中尚未检测到运动缺陷。 Ts65Dn 小鼠中颗粒细胞密度的降低正确地预测了人类的类似病理学； DS 小脑中颗粒细胞密度显着降低是首次报道。因此，影响 DS 小脑发育的 21 号染色体上的基因候选区域被划定为其直系同源物在 Ts65Dn 小鼠中剂量不平衡的基因子集，从而提供了影响 DS 神经解剖表型的基因的第一个定位。通过准确预测 DS 小脑表型，该模型在发育扰动分析中的应用得到了扩展。
Down syndrome (DS) is the most common genetic cause of mental retardation and affects many aspects of brain development. DS individuals exhibit an overall reduction in brain size with a disproportionately greater reduction in cerebellar volume. The Ts65Dn mouse is segmentally trisomic for the distal 12-15 Mb of mouse chromosome 16, a region that shows perfect conserved linkage with human chromosome 21, and therefore provides a genetic model for DS, In this study, high resolution magnetic resonance imaging and histological analysis demonstrate precise neuroanatomical parallels between the DS and the Ts65Dn cerebellum. Cerebellar volume is significantly reduced in Ts65Dn mice due to reduction of both the internal granule layer and the molecular layer of the cerebellum, Granule cell number is further reduced by a decrease in cell density in the internal granule layer, Despite these changes in Ts65Dn cerebellar structure, motor deficits have not been detected in several tests. Reduction in granule cell density in Ts65Dn mice correctly predicts an analogous pathology in humans; a significant reduction in granule cell density in the DS cerebellum is reported here for the first time. The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS. The application of this model for analysis of developmental perturbations is extended by the accurate prediction of DS cerebellar phenotypes.