An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood.
An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood.
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DOI：
10.1016/j.ydbio.2014.12.019
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发表时间：
2015-04-01
影响因子：
2.7
通讯作者：
Targoff, Kimara L.
中科院分区：
文献类型：
--
作者：
George, Vanessa;Colombo, Sophie;Targoff, Kimara L.
定义心室和心房心肌细胞身份的独特特征的时间控制机制对于构建协调的、形态完整的心脏至关重要。我们以前已经证明了nkx基因在维持心室特性中的重要作用，然而，nkx2.5在不同心肌细胞群体中功能的具体时间尚未阐明。在这里，我们表明，在心肌细胞分化的初始阶段，热休克诱导的一种新的转基因品系，Tg（hsp 70 l：nkx2.5-EGFP），导致救援室的形状和身份在nkx2.5−/−胚胎室出现。有趣的是，我们的发现将这种重要的心脏转录因子的早期作用与后期功能联系起来。此外，这些数据表明，nkx2.5也需要在第二心脏领域的心管的形成，反映了在这个群体的分化的时间延迟。因此，我们的研究结果支持一个模型，其中nkx基因诱导下游目标是必要的，以保持室特异性的身份在早期和晚期分化的心肌细胞在离散阶段的心脏形态发生。此外，我们表明，nkx2.5在第一和第二心脏领域的发展过度表达不仅挽救了突变表型，但也是足够的成人心脏的正常功能。总之，这些结果揭示了塑造室特异性心肌细胞的阶段依赖性机制，因此有可能改善心室细胞的体外生成，以治疗心肌梗死和先天性心脏病。
Temporally controlled mechanisms that define the unique features of ventricular and atrial cardiomyocyte identity are essential for the construction of a coordinated, morphologically intact heart. We have previously demonstrated an important role for nkx genes in maintaining ventricular identity, however, the specific timing of nkx2.5 function in distinct cardiomyocyte populations has yet to be elucidated. Here, we show that heat-shock induction of a novel transgenic line, Tg(hsp70l:nkx2.5-EGFP), during the initial stages of cardiomyocyte differentiation leads to rescue of chamber shape and identity in nkx2.5−/− embryos as chambers emerge. Intriguingly, our findings link an early role of this essential cardiac transcription factor with a later function. Moreover, these data reveal that nkx2.5 is also required in the second heart field as the heart tube forms, reflecting the temporal delay in differentiation of this population. Thus, our results support a model in which nkx genes induce downstream targets that are necessary to maintain chamber-specific identity in both early- and late-differentiating cardiomyocytes at discrete stages in cardiac morphogenesis. Furthermore, we show that overexpression of nkx2.5 during first and second heart field development not only rescues the mutant phenotype, but also is sufficient for proper function of the adult heart. Taken together, these results shed new light on the stage-dependent mechanisms that sculpt chamber-specific cardiomyocytes and, therefore, have the potential to improve in vitro generation of ventricular cells to treat myocardial infarction and congenital heart disease.
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DOI：
10.1126/science.1177350
发表时间：
2009-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Domian IJ;Chiravuri M;van der Meer P;Feinberg AW;Shi X;Shao Y;Wu SM;Parker KK;Chien KR
通讯作者：
Chien KR
影响因子：
4.6
作者：
Guner-Ataman, Burcu;Paffett-Lugassy, Noelle;Burns, C. Geoffrey
通讯作者：
Burns, C. Geoffrey
影响因子：
2.7
作者：
Dohn TE;Waxman JS
通讯作者：
Waxman JS
影响因子：
10.5
作者：
AZPIAZU, N;FRASCH, M
通讯作者：
FRASCH, M
影响因子：
2.5
作者：
Hans, Stefan;Freudenreich, Dorian;Brand, Michael
通讯作者：
Brand, Michael