Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development.
Genetic redundancy of GATA factors in the extraembryonic trophoblast lineage ensures the progression of preimplantation and postimplantation mammalian development.
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DOI：
10.1242/dev.145318
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Paul S
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文献类型：
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作者：
Home P;Kumar RP;Ganguly A;Saha B;Milano-Foster J;Bhattacharya B;Ray S;Gunewardena S;Paul A;Camper SA;Fields PE;Paul S
加塔转录因子参与哺乳动物发育过程中细胞命运的确定。在早期哺乳动物胚胎中，GATA 3选择性地在胚外滋养层谱系中表达，并调节基因表达以促进滋养层命运。然而，滋养层特异性GATA 3功能是早期哺乳动物发育所必需的。在这里，使用双条件基因敲除小鼠，我们表明，遗传冗余的Gata 3与paradenogata 2在滋养层祖细胞，确保成功的进展前和植入后哺乳动物的发展。阶段特异性基因缺失滋养层细胞揭示，损失的两个加塔基因，但不是单独的，导致胚胎死亡之前，他们的表达在胚胎适当的发病。使用ChIP-seq和RNA-seq分析，我们定义了GATA 2/GATA 3的全球靶点，并表明它们直接调节大量共同基因，以协调干细胞与分化的滋养层细胞的命运。在滋养层祖细胞中，加塔因子直接调节BMP 4、Nodal和Wnt信号传导组分，其促进胚胎-胚外信号传导串扰，这对于胚胎的发育是必需的。我们的研究提供了遗传学证据，滋养层细胞特异性GATA 2/GATA 3功能受损可能导致早期妊娠失败。总结：在小鼠滋养层发育期间，GATA 2和GATA 3通过直接调节大量共同基因而协同作用，并且共同对于确保滋养层谱系进展很重要。
GATA transcription factors are implicated in establishing cell fate during mammalian development. In early mammalian embryos, GATA3 is selectively expressed in the extraembryonic trophoblast lineage and regulates gene expression to promote trophoblast fate. However, trophoblast-specific GATA3 function is dispensable for early mammalian development. Here, using dual conditional knockout mice, we show that genetic redundancy of Gata3 with paralog Gata2 in trophoblast progenitors ensures the successful progression of both pre- and postimplantation mammalian development. Stage-specific gene deletion in trophoblasts reveals that loss of both GATA genes, but not either alone, leads to embryonic lethality prior to the onset of their expression within the embryo proper. Using ChIP-seq and RNA-seq analyses, we define the global targets of GATA2/GATA3 and show that they directly regulate a large number of common genes to orchestrate stem versus differentiated trophoblast fate. In trophoblast progenitors, GATA factors directly regulate BMP4, Nodal and Wnt signaling components that promote embryonic-extraembryonic signaling cross-talk, which is essential for the development of the embryo proper. Our study provides genetic evidence that impairment of trophoblast-specific GATA2/GATA3 function could lead to early pregnancy failure. Summary: During trophoblast development in mice, GATA2 and GATA3 act synergistically by directly regulating a large number of common genes, and together are important to ensure trophoblast lineage progression.