Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse
Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse
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DOI：
10.1093/cvr/cvq193
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发表时间：
2010-11-01
影响因子：
10.8
通讯作者：
Mohun, Timothy
中科院分区：
文献类型：
--
作者：
Dunlevy, Louisa;Bennett, Mike;Mohun, Timothy
心脏畸形普遍存在于人类21号染色体的三体中[唐氏综合征(DS)]，影响发育中心脏的正常心腔分离。由于缺乏准确的小鼠模型，理解这些缺陷的病因的努力受到了严重阻碍。事实证明，建立这样的模型具有挑战性，因为与人类染色体Hsa21的同源性分布在三条小鼠染色体上。到目前为止，这些工程都没有准确地模拟DS心脏表型的全部范围，特别是房室间隔缺陷(AVSD)引起的深度中断。在这里，我们分析了跨染色体小鼠系TC(Hsa21)1TybEmcf(Tc1)的胚胎所表现出的心脏畸形，除了正常的二倍体小鼠基因组外，Tc1还包含超过90%的染色体Hsa21。使用高分辨率电子显微镜和三维(3D)建模，我们发现Tc1胚胎表现出许多DS中发现的心脏缺陷，包括平衡型房室间隔缺损(具有单个和单独的瓣膜口)、膜和肌间隔缺陷以及流出道和瓣叶异常。心脏畸形的频率(从38%到55%)取决于菌株背景。相比之下，在更有限的小鼠三体模型DP(16Cbr1-ORF9)1Rhr(Ts1Rhr)的胚胎中没有检测到类似的心脏缺陷，这表明唐氏综合征关键区域共线区域的三体区域，包括候选基因DSCAM和DYRK1A，不足以产生DS心脏异常。Tc1小鼠系为研究DS AVSD心脏表型的潜在遗传原因提供了一个合适的模型。
Cardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome.Using high-resolution episcopic microscopy and three-dimensional (3D) modelling, we show that Tc1 embryos exhibit many of the cardiac defects found in DS, including balanced AVSD with single and separate valvar orifices, membranous and muscular ventricular septal defects along with outflow tract and valve leaflet abnormalities. Frequencies of cardiac malformations (ranging from 38 to 55%) are dependent on strain background. In contrast, no comparable cardiac defects were detected in embryos of the more limited mouse trisomy model, Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr), indicating that trisomy of the region syntenic to the Down's syndrome critical region, including the candidate genes DSCAM and DYRK1A, is insufficient to yield DS cardiac abnormalities.The Tc1 mouse line provides a suitable model for studying the underlying genetic causes of the DS AVSD cardiac phenotype.