Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St, Darlinghurst 2010, Australia.
Circ Res. 2010 Sep 17;107(6):715-27. doi: 10.1161/CIRCRESAHA.110.218693. Epub 2010 Jul 22.
The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide.
To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice.
Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2-dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants.
The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1-ErbB1/4-Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation.
心脏基因调控网络（GRN）受转录因子和信号输入控制，但在发育过程中的网络逻辑及其在疾病中的解析仍知之甚少。在发育过程中，位于心内膜的膜结合信号配体神经调节蛋白 1（Nrg）1 对于心室形态发生是必需的。在成人中，Nrg1 可预防心力衰竭并诱导心肌细胞分裂。
通过分析 Nrg1 缺失和功能减弱突变小鼠，了解 Nrg1 在心脏发育中的作用。
尽管腔室限制基因 Hand1 和 Cited1 未能被激活，但 Nrg1 突变体中的腔室域被正确指定。随后，腔室 GRN 衰减，个别基因的衰减模式与已知的模式边界无关。小梁和非小梁心肌均受到影响。网络的消失具有时空动态性，最敏感的区域是左心室的中心部分，GRN 在此完全崩溃。其他区域则受到不同程度的影响。在体外，Nrg1 促进磷酸化-Erk1/2 依赖性转录因子表达、心肌细胞成熟和细胞周期抑制。我们在胚胎中监测心脏 pErk1/2，发现其表达依赖于 Nrg1，且水平与突变体中心脏 GRN 的敏感性相关。
腔室 GRN 本质上不稳定，依赖于心外来源的信号。Nrg1-ErbB1/4-Erk1/2 信号对于小梁和非小梁心肌中 GRN 的某些成分至关重要，这挑战了我们对 Nrg1 功能的理解。由 Nrg1 减少引起的转录衰减模式提示了一种新的心脏转录调控和疾病中功能障碍的机制，可能将生物力学反馈与生长和分化的分子途径联系起来。
