Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development.
Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development.
复制标题
DOI：
10.1016/j.ydbio.2008.11.004
复制
发表时间：
2009-02-15
影响因子：
2.7
通讯作者：
Garg, Vidu
中科院分区：
文献类型：
--
作者：
Maitra, Meenakshi;Schluterman, Marie K.;Nichols, Haley A.;Richardson, James A.;Lo, Cecilia W.;Srivastava, Deepak;Garg, Vidu
先天性心脏病是最常见的出生缺陷类型，发病率为1%。此前，我们描述了一个常染色体显性遗传病家系中的GATA4点突变，该突变与心脏缺陷分离。突变(G296S)表现出生化缺陷，并破坏了Gata4和Tbx5之间的一种新的相互作用。为了确定Gata4和Tbx5在体内是否存在遗传交互作用，我们培育了两个等位基因都杂合的小鼠。我们发现，几乎100%的Gata4和Tbx5杂合子小鼠是胚胎或新生儿致死性的，并有完全性房室间隔缺陷，只有一个房室瓣和心肌变薄。与这种表型一致，Gata4和Tbx5在发育中的心内膜垫和心肌中共同表达。在突变胚胎中，心肌细胞增殖缺陷被鉴定为与心肌发育不良相一致。与GATA4类似，GATA6和Tbx5在胚胎心脏中共表达，转录因子协同激活心房利尿因子启动子。我们证明了GATA6和Tbx5之间的遗传相互作用，并伴有新生儿致死性和心肌变薄的不完全穿透表型。对两组复合杂合子的基因表达分析表明，只有在Gata4/Tbx5杂合子中α-肌球蛋白重链下调。这些发现突出了GATA4和GATA6与Tbx5在体内正常心脏形态发生中的独特遗传相互作用。
Congenital heart disease is the most common type of birth defect with an incidence of 1%. Previously, we described a point mutation in GATA4 that segregated with cardiac defects in a family with autosomal dominant disease. The mutation (G296S) exhibited biochemical deficits and disrupted a novel interaction between Gata4 and Tbx5. To determine if Gata4 and Tbx5 genetically interact in vivo, we generated mice heterozygous for both alleles. We found that nearly 100% of mice heterozygous for Gata4 and Tbx5 were embryonic or neonatal lethal and had complete atrioventricular (AV) septal defects with a single AV valve and myocardial thinning. Consistent with this phenotype, Gata4 and Tbx5 are co-expressed in the developing endocardial cushions and myocardium. In mutant embryos, cardiomyocyte proliferation deficits were identified compatible with the myocardial hypoplasia. Similar to Gata4, Gata6 and Tbx5 are co-expressed in the embryonic heart, and the transcription factors synergistically activate the atrial natiuretic factor promoter. We demonstrate a genetic interaction between Gata6 and Tbx5 with an incompletely penetrant phenotype of neonatal lethality and thin myocardium. Gene expression analyses were performed on both sets of compound heterozygotes and demonstrated downregulation of α-myosin heavy chain only in Gata4/Tbx5 heterozygotes. These findings highlight the unique genetic interactions of Gata4 and Gata6 with Tbx5 for normal cardiac morphogenesis in vivo.
登录
查看更多内容
影响因子：
5.3
作者：
MOLKENTIN, JD;KALVAKOLANU, DV;MARKHAM, BE
通讯作者：
MARKHAM, BE
影响因子：
158.5
作者：
BASSON, CT;COWLEY, GS;SEIDMAN, CE
通讯作者：
SEIDMAN, CE
DOI：
10.1073/pnas.042390499
发表时间：
2002-03-05
影响因子：
11.1
作者：
Gaussin, V;Van de Putte, T;Schneider, MD
通讯作者：
Schneider, MD
影响因子：
10.5
作者：
Jiao, K;Kulessa, H;Hogan, BLM
通讯作者：
Hogan, BLM
影响因子：
10.5
作者：
Kuo, CT;Morrisey, EE;Leiden, JM
通讯作者：
Leiden, JM