HIC2 Is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region
HIC2 Is a Novel Dosage-Dependent Regulator of Cardiac Development Located Within the Distal 22q11 Deletion Syndrome Region
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DOI：
10.1161/circresaha.115.303300
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发表时间：
2014-06-20
影响因子：
20.1
通讯作者：
Scambler, Peter J.
中科院分区：
文献类型：
--
作者：
Dykes, Iain M.;van Bueren, Kelly Lammerts;Scambler, Peter J.
理由：22q11 缺失综合征是由 22 号染色体上的低拷贝重复之间的重组引起的。典型的缺失会导致与先天性心血管疾病相关的 TBX1 半合子性。典型缺失区域远端的缺失会导致相似的心脏表型，但缺乏该综合征的心外特征，这表明第二个单倍体不足的基因映射到该区间。 目的：转录因子 HIC2 在大多数远端缺失以及少数典型缺失中丢失。我们使用小鼠模型来检验 HIC2 半合性导致先天性心脏病的假设。方法和结果：我们创建了 Hic2 的基因陷阱小鼠等位基因。基因陷阱报告基因在心脏形态发生的整个关键阶段都在心脏中表达。基因陷阱等位基因的纯合性在胚胎 E10.5 天之前是胚胎致死性的，而杂合性条件则表现出部分渗透的晚期致死性。三分之一的杂合胚胎具有心脏表型。 MRI 显示室间隔缺损伴主动脉跨过。条件靶向表明 Nkx2.5+ 和 Mesp1+ 心血管祖细胞谱系中需要 Hic2。微阵列分析显示 Bmp10 的表达增加。结论：我们的结果表明 Hic2 在心脏发育中具有新的作用。 Hic2 是远端 22q11 间隔内第一个在小鼠中表现出单倍体不足心脏表型的基因。我们的数据表明，HIC2 单倍体不足可能导致远端 22q11 缺失综合征中出现的心脏缺陷。
Rationale: 22q11 deletion syndrome arises from recombination between low-copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack in extracardiac features of the syndrome, suggesting that a second haploinsufficient gene maps to this interval.Objective: The transcription factor HIC2 is lost in most distal deletions, as well as in a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease.Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5, whereas the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. MRI demonstrated a ventricular septal defect with over-riding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages. Microarray analysis revealed increased expression of Bmp10.Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggest that HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome.