Postnatal lethality and cardiac anomalies in the Ts65Dn Down Syndrome mouse model
Postnatal lethality and cardiac anomalies in the Ts65Dn Down Syndrome mouse model
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DOI：
10.1007/s00335-006-0032-8
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发表时间：
2006-10-01
期刊：
影响因子：
2.5
通讯作者：
Moore, Clara S.
中科院分区：
文献类型：
--
作者：
Moore, Clara S.
Ts65Dn小鼠是唐氏综合征（DS）的充分研究的模型。易位染色体T17（16）终止（称为T65Dn）的存在导致小鼠16号染色体远端区域上超过100个基因的三体剂量失衡。这种剂量不平衡，超过一半的人类21号染色体（Hsa21）的直系同源物，导致三体小鼠中的几种表型，使人联想到DS。仔细检查新生儿在一个新成立的Ts65Dn殖民地表明高出生后致死率。尽管之前报道T65 Dn染色体的传播率为20%-40%，但所有后代的基因分型表明出生时的传播接近孟德尔传播和生存预期的50%。值得注意的是，在有母亲照顾的窝仔中，允许一些幼崽存活，出生后死亡主要发生在继承T65Dn标记染色体的幼崽中。出生后48小时内的选择性丢失使标记染色体的传递率从出生时的49%降低到断奶时的34%。大体形态学检查显示心血管异常，即，右主动脉弓合并室间隔缺损占三体新生儿尸体的8.3%。这是一个有趣的发现，因为HSA22的DiGeorge区域的直系同源物（其被认为有助于在16三体小鼠中观察到的主动脉弓异常）在Ts65Dn小鼠中不是三重的。这些新的观察结果表明，Ts65Dn小鼠模型DS不仅在其先前描述的表型，但也与出生后死亡率升高和先天性心脏畸形，可能会导致死亡率。
The Ts65Dn mouse is a well-studied model for Down syndrome (DS). The presence of the translocation chromosome T17(16) stop (referred to as T65Dn) produces a trisomic dosage imbalance for over 100 genes on the distal region of mouse Chromosome 16. This dosage imbalance, with more than half of the orthologs of human Chromosome 21 (Hsa21), causes several phenotypes in the trisomic mice that are reminiscent of DS. Careful examination of neonates in a newly established Ts65Dn colony indicated high rates of postnatal lethality. Although the transmission rate for the T65Dn chromosome has been previously reported as 20%-40%, genotyping of all progeny indicates transmission at birth is near the 50% expected with Mendelian transmission and survival. Remarkably, in litters with maternal care that allowed survival of some pups, postnatal lethality occurred primarily in pups that inherited the T65Dn marker chromosome. This selective loss within 48 h of birth reduced the transmission of the marker chromosome from 49% at birth to 34% at weaning. Gross morphologic examination revealed cardiovascular anomalies, i.e., right aortic arch accompanied by septal defects, in 8.3% of the trisomic newborn cadavers examined. This is an intriguing finding because the orthologs of the DiGeorge region of HSA22, which are posited to contribute to the aortic arch abnormalities seen in trisomy 16 mice, are not triplicated in Ts65Dn mice. These new observations suggest that the Ts65Dn mouse models DS not only in its previously described phenotypes but also with elevated postnatal lethality and congenital heart malformations that may contribute to mortality.