Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2013 Aug 23;288(34):24429-40. doi: 10.1074/jbc.M113.463083. Epub 2013 Jul 8.
GATA and Friend of GATA (FOG) form a transcriptional complex that plays a key role in cardiovascular development in both fish and mammals. In the present study we demonstrate that the basic helix-loop-helix transcription factor Atonal homolog 8 (Atoh8) is required for development of the heart in fish but not in mice. Genetic studies reveal that Atoh8 interacts specifically with Gata4 and Fog1 during development of the heart and swim bladder in the fish. Biochemical studies reveal that ATOH8, GATA4, and FOG2 associate in a single complex in vitro. In contrast to fish, ATOH8-deficient mice exhibit normal cardiac development and loss of ATOH8 does not alter cardiac development in Gata4(+/-) mice. This species difference in the role of ATOH8 is explained in part by LacZ and GFP reporter alleles that reveal restriction of Atoh8 expression to atrial but not ventricular myocardium in the mouse. Our findings identify ATOH8 as a novel regulator of GATA-FOG function that is required for cardiac development in the fish but not the mouse. Whether ATOH8 modulates GATA-FOG function at other sites or in more subtle ways in mammals is not yet known.
GATA 和 GATA 的朋友（FOG）形成一个转录复合物，在鱼类和哺乳动物的心血管发育中发挥关键作用。在本研究中，我们证明了基本螺旋-环-螺旋转录因子 Atonal 同源物 8（Atoh8）在鱼类心脏发育中是必需的，但在小鼠中不是必需的。遗传研究表明，Atoh8 在鱼类心脏和鳔的发育过程中与 Gata4 和 Fog1 特异性相互作用。生化研究表明，ATOH8、GATA4 和 FOG2 在体外形成单一复合物。与鱼类不同，缺乏 ATOH8 的小鼠表现出正常的心脏发育，并且 ATOH8 的缺失不会改变 Gata4(+/-)小鼠的心脏发育。这种 ATOH8 作用的物种差异部分可以通过 LacZ 和 GFP 报告基因等位基因来解释，这些等位基因表明 Atoh8 在小鼠中的表达仅限于心房而不是心室心肌。我们的发现确定 ATOH8 是 GATA-FOG 功能的一个新的调节因子，它在鱼类的心脏发育中是必需的，但在小鼠中不是必需的。ATOH8 是否在其他部位或以更微妙的方式调节哺乳动物的 GATA-FOG 功能尚不清楚。
