Qian Li, Mohapatra Bhagyalaxmi, Akasaka Takeshi, Liu Jiandong, Ocorr Karen, Towbin Jeffrey A, Bodmer Rolf
Development and Aging Program, Del E. Webb Neuroscience, Aging and Stem Cell Research Center (NASCR), Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19833-8. doi: 10.1073/pnas.0808705105. Epub 2008 Dec 11.
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.
神经漫游者/Tbx20（nmr）基因是心脏T盒转录因子，从果蝇到人类在进化上保守。与其他已知的先天性心脏病基因，包括tinman/Nkx2 - 5、背交叉/Tbx5/6和pannier/Gata4/6一起，它们对胚胎心脏的特化和形态发生很重要。果蝇心脏已被证明是研究参与建立和维持成体心脏结构完整性的基因以及参与维持生理功能的基因的优秀模型。利用这个模型，我们已确定nmr是成年果蝇心脏中维持正常肌原纤维结构和心脏生理功能所需的基因。此外，我们发现nmr与其他心脏转录因子，包括tinman/Nkx2 - 5，在调节心脏性能、节律性和心肌细胞结构方面存在协同相互作用，这让人想起小鼠中的类似相互作用。这表明这个心脏转录因子网络在成体心脏的遗传控制中具有显著保守的作用。此外，nmr - tinman相互作用也影响潜在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在三例散发性和两例家族性病例中发现了TBX20变体，而对照组未发现。这些发现表明果蝇心脏可能作为参与人类心脏病的候选基因的标识符。
