Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits.
Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits.
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DOI：
10.1093/hmg/ddt446
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发表时间：
2014-02
影响因子：
3.5
通讯作者：
Li Zhang;Kai Meng;Xiaoling Jiang;Chunhong Liu;A. Pao;P. Belichenko;A. Kleschevnikov;S. Josselyn;P. Liang;Ping Ye;W. Mobley;Y. E. Yu
中科院分区：
文献类型：
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作者：
Li Zhang;Kai Meng;Xiaoling Jiang;Chunhong Liu;A. Pao;P. Belichenko;A. Kleschevnikov;S. Josselyn;P. Liang;Ping Ye;W. Mobley;Y. E. Yu
21三体综合征（唐氏综合征，DS）是发育性认知缺陷最常见的遗传病因，所谓的唐氏综合征关键区域（DSCR）被认为是这种表型的主要决定因素。人类21号染色体（Hsa21）上的区域在小鼠10号（Mmu10）、16号（Mmu16）和17号（Mmu17）染色体上是同线性保守的。DSCR在Mmu16上的Cbr1和Fam3b基因之间是保守的。Ts65Dn小鼠在Mmu16上携带约100个Hsa21基因同源物的三个拷贝，并在莫里斯水迷宫和海马长时程增强（LTP）中表现出损伤。在Ts65Dn小鼠中将Cbr1 - Fam3b区域恢复为两个拷贝挽救了这些表型。在本研究中，我们在Dp(16)1Yey/+小鼠中对Cbr1 - Fam3b区域进行了类似的转换，该小鼠在Mmu16上的所有约115个Hsa21基因同源物都是三份的，这也导致莫里斯水迷宫和海马LTP中的野生型表型恢复。然而，在一个完整模型Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+中，将Cbr1 - Fam3b区域恢复为两个拷贝未能产生类似的表型恢复。但是，令人惊讶的是，在完整模型中将Cbr1 - Fam3b区域和Mmu17上的Hsa21同源区域都恢复为两个拷贝确实将这些表型完全恢复到野生型水平。我们的结果表明，Mmu17上的Hsa21同源区域是与DS相关的发育性认知缺陷的主要决定因素。因此，在小鼠模型中包含这个Hsa21同源区域的三个拷贝对于揭示DS相关发育性认知缺陷的潜在机制以及开发针对这种临床表现的有效干预措施是必要的。
Trisomy 21 (Down syndrome, DS) is the most common genetic cause of developmental cognitive deficits, and the so-called Down syndrome critical region (DSCR) has been proposed as a major determinant of this phenotype. The regions on human chromosome 21 (Hsa21) are syntenically conserved on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. DSCR is conserved between the Cbr1 and Fam3b genes on Mmu16. Ts65Dn mice carry three copies of ∼100 Hsa21 gene orthologs on Mmu16 and exhibited impairments in the Morris water maze and hippocampal long-term potentiation (LTP). Converting the Cbr1-Fam3b region back to two copies in Ts65Dn mice rescued these phenotypes. In this study, we performed similar conversion of the Cbr1-Fam3b region in Dp(16)1Yey/+ mice that is triplicated for all ∼115 Hsa21 gene orthologs on Mmu16, which also resulted in the restoration of the wild-type phenotypes in the Morris water maze and hippocampal LTP. However, converting the Cbr1-Fam3b region back to two copies in a complete model, Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+, failed to yield the similar phenotypic restorations. But, surprisingly, converting both the Cbr1-Fam3b region and the Hsa21 orthologous region on Mmu17 back to two copies in the complete model did completely restore these phenotypes to the wild-type levels. Our results demonstrated that the Hsa21 orthologous region on Mmu17 is a major determinant of DS-related developmental cognitive deficits. Therefore, the inclusion of the three copies of this Hsa21 orthologous region in mouse models is necessary for unraveling the mechanism underlying DS-associated developmental cognitive deficits and for developing effective interventions for this clinical manifestation.