A threshold of GATA4 and GATA6 expression is required for cardiovascular development
A threshold of GATA4 and GATA6 expression is required for cardiovascular development
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DOI：
10.1073/pnas.0604604103
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发表时间：
2006-07-25
影响因子：
11.1
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
Xin, Mei;Davis, Christopher A.;Olson, Eric N.
锌指转录因子GATA 4和GATA 6在胚胎发育中起着关键作用。缺乏GATA 4的小鼠胚胎在胚胎第8.5天死亡，因为腹前肠闭合失败和心脏裂，而GATA 6对内脏内胚层的发育至关重要。尽管GATA 4或GATA 6无效等位基因杂合的小鼠是正常的，但我们发现GATA 4和GATA 6的复合杂合性导致E13.5的胚胎死亡，并伴有一系列心血管缺陷，包括薄壁心肌、心室和室间隔缺损以及平滑肌发育异常。GATA 4/GATA 6双杂合子突变胚胎中的心肌发育不全与心肌细胞增殖减少、肌原性转录因子MEF 2C（肌细胞增强因子2C）表达减少和β-肌球蛋白重链表达下调（心肌收缩力的关键决定因素）相关。这些发现揭示了GATA 4和GATA 6活性的阈值，这是发育中的心血管系统基因表达所必需的，并强调了隐性突变扰乱心血管发育微妙调节的潜力。
The zinc-finger transcription factors GATA4 and GATA6 play critical roles in embryonic development. Mouse embryos lacking GATA4 die at embryonic day (E) 8.5 because of failure of ventral foregut closure and cardiac bifida, whereas GATA6 is essential for development of the visceral endoderm. Although mice that are heterozygous for either a GATA4 or GATA6 null allele are normal, we show that compound heterozygosity of GATA4 and GATA6 results in embryonic lethality by E13.5 accompanied by a spectrum of cardiovascular defects, including thin-walled myocardium, ventricular and aortopulmonary septal defects, and abnormal smooth muscle development. Myocardial hypoplasia in GATA4/GATA6 double heterozygous mutant embryos is associated with reduced proliferation of cardiomyocytes, diminished expression of the myogenic transcription factor MEF2C (myocyte enhancer factor 2C), and down-regulation of beta-myosin heavy chain expression, a key determinant of cardiac contractility. These findings reveal a threshold of GATA4 and GATA6 activity that is required for gene expression in the developing cardiovascular system and underscore the potential of recessive mutations to perturb the delicate regulation of cardiovascular development.