Division of Developmental Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Cardiovasc Res. 2010 Nov 1;88(2):287-95. doi: 10.1093/cvr/cvq193. Epub 2010 Jun 16.
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.
21 号人类染色体三体症（唐氏综合征，DS）中普遍存在心脏畸形，影响心脏发育过程中正常心室的分隔。由于缺乏准确的小鼠模型，对这些缺陷病因的研究受到严重阻碍。由于与人类染色体 Hsa21 的同线性分布在三个小鼠染色体上，因此建立此类模型一直具有挑战性。迄今为止，所建立的这些模型都无法准确模拟 DS 的全谱心脏表型，特别是房室间隔缺损（AVSD）导致的严重破坏。在这里，我们分析了转染色体小鼠系 Tc(Hsa21)1TybEmcf（Tc1）胚胎所表现出的心脏畸形，该系除了正常的二倍体小鼠基因组外，还包含超过 90%的人类染色体 Hsa21。
使用高分辨率的外照显微镜和三维（3D）建模，我们显示 Tc1 胚胎表现出许多在 DS 中发现的心脏缺陷，包括平衡的 AVSD 伴有单一和独立的瓣孔、膜性和肌性室间隔缺损以及流出道和瓣膜叶异常。心脏畸形的频率（范围为 38%至 55%）取决于品系背景。相比之下，在更为有限的小鼠三体模型 Dp(16Cbr1-ORF9)1Rhr（Ts1Rhr）的胚胎中未检测到类似的心脏缺陷，表明与唐氏综合征关键区域同线性的区域的三倍体，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合适的模型。
