Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia.
Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia.
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DOI：
10.1007/s00395-013-0339-z
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发表时间：
2013-03
影响因子：
9.5
通讯作者：
Rappold G
中科院分区：
文献类型：
--
作者：
Hoffmann S;Berger IM;Glaser A;Bacon C;Li L;Gretz N;Steinbeisser H;Rottbauer W;Just S;Rappold G
心脏的节律是由心脏的主要起搏器--窦房结中的一组特殊细胞启动和调节的。窦房结发育的异常可导致心率不齐(心律失常)。虽然已经鉴定了几个对SAN形成重要的关键基因，但我们对控制SAN发育的转录网络的了解仍处于相对早期的阶段。同源结构域转录因子Shox2参与了SAN的规范和模式形成。虽然在小鼠中Shox2基因敲除会由于严重的心脏缺陷(包括窦房结发育不正常)而导致胚胎死亡，但在斑马鱼中Shox2基因敲除会导致心率减慢(心动过缓)。为了更深入地了解与Shox2相关的分子途径，我们利用基因芯片实验比较了野生型和Shox2−/−心脏右心房的基因表达水平，并确定LIM同源结构域转录因子Islet1(Isl1)是其可能的靶基因之一。经整体原位杂交证实，在SHOX2−/−心脏中IsL1的表达下调，并将受影响的区域缩小到窦房结。利用荧光素酶报告基因分析和EMSA研究，我们在Isl1基因座内含子2中鉴定了两个SHOX2结合位点。我们还以斑马鱼为模型系统，通过用Isl1挽救Shox2介导的心动过缓表型，为Isl1作为Shox2的转录靶点提供了功能证据。我们的发现证明了心脏中Shox2和Isl1之间的一种新的上位关系，对窦房结的形成和心跳具有重要的发育影响。本文的在线版本(doi：10.1007/s00395-0130339-z)包含补充材料，授权用户可以使用。
The heart’s rhythm is initiated and regulated by a group of specialized cells in the sinoatrial node (SAN), the primary pacemaker of the heart. Abnormalities in the development of the SAN can result in irregular heart rates (arrhythmias). Although several of the critical genes important for SAN formation have been identified, our understanding of the transcriptional network controlling SAN development remains at a relatively early stage. The homeodomain transcription factor Shox2 is involved in the specification and patterning of the SAN. While the Shox2 knockout in mice results in embryonic lethality due to severe cardiac defects including improper SAN development, Shox2 knockdown in zebrafish causes a reduced heart rate (bradycardia). In order to gain deeper insight into molecular pathways involving Shox2, we compared gene expression levels in right atria of wildtype and Shox2 −/− hearts using microarray experiments and identified the LIM homeodomain transcription factor Islet1 (Isl1) as one of its putative target genes. The downregulation of Isl1 expression in Shox2 −/− hearts was confirmed and the affected region narrowed down to the SAN by whole-mount in situ hybridization. Using luciferase reporter assays and EMSA studies, we identified two specific SHOX2 binding sites within intron 2 of the ISL1 locus. We also provide functional evidence for Isl1 as a transcriptional target of Shox2 by rescuing the Shox2-mediated bradycardia phenotype with Isl1 using zebrafish as a model system. Our findings demonstrate a novel epistatic relationship between Shox2 and Isl1 in the heart with important developmental consequences for SAN formation and heart beat. The online version of this article (doi:10.1007/s00395-013-0339-z) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.95.5.2406
发表时间：
1998-03-03
影响因子：
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作者：
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