GATA5 interacts with GATA4 and GATA6 in outflow tract development
GATA5 interacts with GATA4 and GATA6 in outflow tract development
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DOI：
10.1016/j.ydbio.2011.07.037
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发表时间：
2011-10-15
影响因子：
2.7
通讯作者：
Nemer, Mona
中科院分区：
文献类型：
--
作者：
Laforest, Brigitte;Nemer, Mona
转录因子加塔家族的成员是心脏发育的关键调节因子，其中2个基因突变。GATA 4和GATA 6与人类流出道和间隔缺损有关。心脏以部分重叠的模式表达3种加塔因子，GATA 4、5和6。在这里，我们报告说，化合物Gata 4/Gata 5和Gata 5/Gata 6突变体死于胚胎或围产期由于严重的先天性心脏缺陷。几乎所有的Gata 4（+/-）Gata 5（+/-）突变胚胎都有双出口右心室（DORV），大的室间隔缺损（VSD）以及肥大的二尖瓣和三尖瓣。只有25%的双复合Gata 4/Gata 5杂合子存活到成年，这些小鼠患有主动脉瓣狭窄。Gata 5和Gata 6等位基因的复合缺失也导致与主动脉下VSD相关的DORV。在复合杂合子胚胎中，几个对内皮细胞和心肌细胞分化重要的转录因子，如Tbx 20，Mef 2c，Hey 1和Hand 2的表达降低。这些发现表明，Gata 5和其他2个心脏加塔因子在内膜垫形成和流出道形态发生中存在重要的遗传相互作用。这些数据将GATA 5确定为先天性心脏病的潜在遗传修饰剂，并为阐明一类重要的人类出生缺陷的遗传基础提供了见解。(C)2011 Elsevier Inc. All rights reserved.
Members of the GATA family of transcription factors are critical regulators of heart development and mutations in 2 of them. GATA4 and GATA6 are associated with outflow tract and septal defects in human. The heart expresses 3 GATA factors, GATA4, 5 and 6 in a partially overlapping pattern. Here, we report that compound Gata4/Gata5 and Gata5/Gata6 mutants die embryonically or perinatally due to severe congenital heart defects. Almost all Gata4(+/-)Gata5(+/-) mutant embryos have double outlet right ventricles (DORV), large ventricular septal defects (VSD) as well as hypertrophied mitral and tricuspid valves. Only 25% of double compound Gata4/Gata5 heterozygotes survive to adulthood and these mice have aortic stenosis. Compound loss of a Gata5 and a Gata6 allele also leads to DORVs associated with subaortic VSDs. Expression of several transcription factors important for endocardial and myocardial cell differentiation, such as Tbx20, Mef2c, Hey1 and Hand2, was reduced in compound heterozygote embryos. These findings suggest the existence of important genetic interactions between Gata5 and the 2 other cardiac GATA factors in endocardial cushion formation and outflow tract morphogenesis. The data identify GATA5 as a potential genetic modifier of congenital heart disease and provide insight for elucidating the genetic basis of an important class of human birth defects. (C) 2011 Elsevier Inc. All rights reserved.