GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo
GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo
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DOI：
10.1101/gad.12.22.3579
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发表时间：
1998-11-15
影响因子：
10.5
通讯作者：
Parmacek, MS
中科院分区：
文献类型：
--
作者：
Morrisey, EE;Tang, ZH;Parmacek, MS
GATA6属于锌指转录因子家族，在转导调控脊椎动物细胞分化和胚胎形态发生的核事件中发挥重要作用。为了研究GATA6在胚胎发育过程中的功能，采用基因打靶技术产生了GATA6缺陷型（GATA6(-/-)）胚胎干细胞以及GATA6基因发生无效突变的小鼠。源自GATA6(-/-)胚胎干细胞的分化胚状体缺乏内脏内胚层覆盖层，并且严重减弱或无法表达编码早期和晚期内胚层标志物的基因，包括HNF4、GATA4、甲胎蛋白（AFP）和HNF3β。纯合的GATA6(-/-)小鼠在胚胎第6.5天到第7.5天之间死亡，在内胚层分化方面表现出特定缺陷，包括GATA4表达严重下调以及HNF4基因不表达。此外，在GATA6缺陷型胚胎的外胚层中观察到广泛的程序性细胞死亡，这一现象在HNF4缺陷型胚胎中也有发现。与这些数据一致的是，在非内胚层细胞中强制表达GATA6可激活HNF4启动子。最后，为了研究GATA6在胚胎发育后期的功能，构建了GATA6(-/-)-C57BL/6嵌合小鼠，带有lacZ标记的GATA6(-/-)胚胎干细胞可参与除内胚层衍生的支气管上皮之外的所有胚胎组织。综上所述，这些数据表明在一个调控内脏内胚层分化的转录级联反应中，GATA6位于HNF4的上游。此外，这些数据还证明GATA6对于内胚层衍生的支气管上皮的形成是必需的。
GATA6 belongs to a family of zinc finger transcription factors that play important roles in transducing nuclear events that regulate cellular differentiation and embryonic morphogenesis in vertebrate species. To examine the function of GATA6 during embryonic development, gene targeting was used to generate GATA6-deficient (GATA6(-/-)) ES cells and mice harboring a null mutation in GATA6. Differentiated embryoid bodies derived from GATA6(-/-) ES cells lack a covering layer of visceral endoderm and severely attenuate, or fail to express, genes encoding early and late endodermal markers, including HNF4, GATA4, rw-fetoprotein (AFP), and HNF3 beta. Homozygous GATA6(-/-) mice died between embryonic day (E) 6.5 and E7.5 and exhibited a specific defect in endoderm differentiation including severely down-regulated expression of GATA4 and absence of HNF4 gene expression. Moreover, widespread programmed cell death was observed within the embryonic ectoderm of GATA6-deficient embryos, a finding also observed in HNF4-deficient embryos. Consistent with these data, forced expression of GATA6 activated the HNF4 promoter in nonendodermal cells. Finally, to examine the function of GATA6 during later embryonic development, GATA6(-/-)-C57BL/6 chimeric mice were generated, lacZ-tagged GATA6(-/-) ES cells contributed to all embryonic tissues with the exception of the endodermally derived bronchial epithelium. Taken together, these data suggest a model in which GATA6 lies upstream of HNF4 in a transcriptional cascade that regulates differentiation of the visceral endoderm. In addition, these data demonstrate that GATA6 is required for establishment of the endodermally derived bronchial epithelium.