The ATP-sensitive potassium (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman
The ATP-sensitive potassium (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman
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DOI：
10.1073/pnas.0603098103
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发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Bodmer, Rolf
中科院分区：
文献类型：
--
作者：
Akasaka, Takeshi;Klinedinst, Susan;Bodmer, Rolf
同源框转录因子Tinman在心脏发育的启动中起着重要作用。Tinman后来的功能，包括参与心脏生理学的靶基因，研究得较少。我们专注于dSUR基因，它编码一种在心脏中表达的ATP结合盒跨膜蛋白。哺乳动物SUR基因与K-ATP（ATP敏感钾）通道相关，其参与代谢稳态。我们提供的实验证据表明，Tinman直接调节dSUR在发育中的心脏表达。我们确定了一个顺式调节元件的第一内含子的dSUR，其中包含Tinman共识结合位点，是足够的忠实dSUR表达在苍蝇的心肌。该元件的定点诱变表明，这些Tinman位点对dSUR表达至关重要，进一步的遗传操作表明，加塔转录因子Pannier协同参与体内心脏限制性dSUR表达。对dSUR敲除果蝇的生理分析支持dSUR对缺氧应激和起搏诱导的心力衰竭起保护作用的观点。由于dSUR表达随年龄的增长而显著降低，因此它可能是果蝇心脏衰老表型中的一个因素。dSUR提供了一个模型，用于说明心肌细胞定型的胚胎调节因子如何有助于建立和维持心脏性能。
The homeobox transcription factor Tinman plays an important role in the initiation of heart development. Later functions of Tinman, including the target genes involved in cardiac physiology, are less well studied. We focused on the dSUR gene, which encodes an ATP-binding cassette transmembrane protein that is expressed in the heart. Mammalian SUR genes are associated with K-ATP (ATP-sensitive potassium) channels, which are involved in metabolic homeostasis. We provide experimental evidence that Tinman directly regulates dSUR expression in the developing heart. We identified a cis-regulatory element in the first intron of dSUR, which contains Tinman consensus binding sites and is sufficient for faithful dSUR expression in the fly's myocardium. Site-directed mutagenesis of this element shows that these Tinman sites are critical to dSUR expression, and further genetic manipulations suggest that the GATA transcription factor Pannier is synergistically involved in cardiac-restricted dSUR expression in vivo. Physiological analysis of dSUR knock-down flies supports the idea that dSUR plays a protective role against hypoxic stress and pacing-induced heart failure. Because dSUR expression dramatically decreases with age, it is likely to be a factor involved in the cardiac aging phenotype of Drosophila. dSUR provides a model for addressing how embryonic regulators of myocardial cell commitment can contribute to the establishment and maintenance of cardiac performance.