Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease
Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease
复制标题
DOI：
10.1073/pnas.0808705105
复制
发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Bodmer, Rolf
中科院分区：
文献类型：
--
作者：
Qian, Li;Mohapatra, Bhagyalaxmi;Bodmer, Rolf
neuromancer/Tbx 20（nmr）基因是从果蝇到人类进化上保守的心脏T-box转录因子。沿着其他已知的先天性心脏病基因，包括tinman/Nkx 2 -5、dorsocross/Tbx 5/6和pannier/Gata 4/6，它们对于胚胎心脏的特化和形态发生是重要的。果蝇心脏已被证明是一个很好的模型，研究基因参与建立和维持成年心脏的结构完整性，以及基因参与维持生理功能。利用这个模型，我们已经确定了成年果蝇心脏中维持正常肌原纤维结构和心脏生理所需的nmr基因。此外，我们发现核磁共振和其他心脏转录因子，包括tinman/Nkx 2 -5，在调节心脏性能，节律和心肌细胞结构，让人想起在小鼠中类似的相互作用之间的协同作用。这表明，在成人心脏的遗传控制中，心脏转录因子网络具有非常保守的作用。此外，nmr-tinman相互作用也影响潜在的下游效应物，如离子通道的表达。有趣的是，对扩张型心肌病和先天性心脏病患者的基因筛查发现，在三个散发性和两个家族性病例中发现了TBX 20变异，而在对照组中没有发现。这些发现表明，苍蝇心脏可能作为参与人类心脏病的候选基因的标识符。
neuromancer/Tbx20 (nmr) genes are cardiac T-box transcription factors that are evolutionarily conserved from flies to humans. Along with other known congenital heart disease genes, including tinman/Nkx2-5, dorsocross/Tbx5/6, and pannier/Gata4/6, they are important for specification and morphogenesis of the embryonic heart. The Drosophila heart has proven to be an excellent model to study genes involved in establishing and maintaining the structural integrity of the adult heart, as well as genes involved in maintaining physiological function. Using this model, we have identified nmr as a gene required in adult fly hearts for the maintenance of both normal myofibrillar architecture and cardiac physiology. Moreover, we have discovered synergistic interactions between nmr and other cardiac transcription factors, including tinman/Nkx2-5, in regulating cardiac performance, rhythmicity, and cardiomyocyte structure, reminiscent of similar interactions in mice. This suggests a remarkably conserved role for this network of cardiac transcription factors in the genetic control of the adult heart. In addition, nmr-tinman interactions also influence the expression of potential downstream effectors, such as ion channels. Interestingly, genetic screening of patients with dilated cardiomyopathy and congenital heart disease has revealed TBX20 variants in three sporadic and two familial cases that were not found in controls. These findings suggest that the fly heart might serve as an identifier of candidate genes involved in human heart disease.