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首页> 外文期刊>Molecular and Cellular Biology >GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium
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GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium

机译：GATA4是细胞周期蛋白D2和Cdk4的直接转录激活因子，是心脏前场衍生心肌中心肌细胞增殖所必需的

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摘要

The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes.
机译：前心脏场（AHF）包括一组中胚层祖细胞，这些细胞被添加到新生的线性心脏中，从而在哺乳动物和鸟类中产生大部分右心室，室间隔和流出道。锌指转录因子GATA4在AHF衍生物中充当心脏转录因子网络的组成部分。除了其在心脏分化中的作用外，心肌细胞复制还需要GATA4，尽管之前尚未确定增殖所需的GATA4转录靶标。在本研究中，我们仅破坏了AHF及其衍生物中的 Gata4 功能。 Gata4 AHF基因敲除小鼠在胚胎第13.5天时死亡，并表现出右心室心肌和室间隔的发育不全，并表现出严重的室间隔缺损。 AHF中 Gata4 功能的丧失导致右心室肌细胞增殖减少，我们通过微阵列分析发现了许多依赖于 Gata4 的细胞周期基因。我们显示，GATA4是右心室中细胞周期蛋白D2，细胞周期蛋白A2和Cdk4表达所必需的，并且 Cyclin D2 和 Cdk4 启动子通过多个途径被GATA4结合和激活每个基因的近端启动子中共有的GATA结合位点。这些发现将 Cyclin D2 和 Cdk4 确立为GATA4的直接转录靶标，并支持GATA4通过协调调控许多细胞周期基因来控制心肌细胞增殖的模型。

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