GATA4 transcription factor is required for ventral morphogenesis and heart tube formation
GATA4 transcription factor is required for ventral morphogenesis and heart tube formation
复制标题
DOI：
10.1101/gad.11.8.1048
复制
发表时间：
1997-04-15
影响因子：
10.5
通讯作者：
Leiden, JM
中科院分区：
文献类型：
--
作者：
Kuo, CT;Morrisey, EE;Leiden, JM
已有研究表明GATA 4转录因子在哺乳动物心脏发育中起着重要的调控作用。在本报告所述的研究中，我们使用基因靶向来产生GATA 4缺陷小鼠。纯合子GATA 4缺陷型（GATA 4（-/-））小鼠在交配后（dpc）8.5至10.5天死亡。GATA 4（-/-）胚胎在喙尾和侧腹折叠方面都表现出严重的缺陷，这反映在腹侧体模式的普遍破坏上。这导致了有组织的前肠和前肠孔的缺陷形成，羊膜腔和卵黄囊的闭合失败，以及腹侧心包腔和心管的均匀缺乏。对GATA 4（-/-）小鼠心脏发育的分析表明，这些胚胎发育了内脏中胚层，其分化为表达收缩蛋白的原始心肌细胞。然而，与观察到的腹侧形态发生缺陷一致，这些GATA 4（-/-）前心肌细胞未能迁移到腹侧中线形成线性心管，而是在胚胎的前部和背外侧区域形成异常的心脏结构。GATA 4（-/-）前心肌细胞腹侧迁移的缺陷不是细胞内在的，因为GATA 4（-/-）心肌细胞和内皮细胞在GATA 4（-/-）-C57 BL/6嵌合小鼠的心脏中聚集。综上所述，这些结果表明，GATA 4不是心脏细胞谱系的特化所必需的。然而，他们定义了GATA 4在调节正常心脏形态发生所需的胚胎的喙尾和侧腹折叠中的关键作用。
Previous studies have suggested that the GATA4 transcription factor plays an important role in regulating mammalian cardiac development. In the studies described in this report we have used gene targeting to produce GATA4-deficient mice. Homozygous GATA4-deficient (GATA4(-/-)) mice died between 8.5 and 10.5 days post coitum (dpc). GATA4(-/-) embryos displayed severe defects in both rostral-to-caudal and lateral-to-ventral folding, which were reflected in a generalized disruption of the ventral body pattern. This resulted in the defective formation of an organized foregut and anterior intestinal pore, the failure to close both the amniotic cavity and yolk sac, and the uniform lack of a ventral pericardial cavity and heart tube. Analysis of cardiac development in the GATA4(-/-) mice demonstrated that these embryos developed splanchnic mesoderm, which differentiated into primitive cardiac myocytes that expressed contractile proteins. However, consistent with the observed defect in ventral morphogenesis, these GATA4(-/-) procardiomyocytes failed to migrate to the ventral midline to form a linear heart tube and instead formed aberrant cardiac structures in the anterior and dorsolateral regions of the embryo. The defect in ventral migration of the GATA4(-/-) procardiomyocytes was not cell intrinsic because GATA4(-/-) cardiac myocytes and endocardial cells populated the hearts of GATA4(-/-)-C57BL/6 chimeric mice. Taken together, these results demonstrated that GATA4 is not essential for the specification of the cardiac cell lineages. However, they define a critical role for GATA4 in regulating the rostral-to-caudal and lateral-to-ventral folding of the embryo that is needed for normal cardiac morphogenesis.