Neuregulin 1 Sustains the Gene Regulatory Network in Both Trabecular and Nontrabecular Myocardium
Neuregulin 1 Sustains the Gene Regulatory Network in Both Trabecular and Nontrabecular Myocardium
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DOI：
10.1161/circresaha.110.218693
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发表时间：
2010-09-17
影响因子：
20.1
通讯作者：
Harvey, Richard P.
中科院分区：
文献类型：
--
作者：
Lai, Donna;Liu, Xifu;Harvey, Richard P.
理由：心脏基因调控网络（GRN）受转录因子和信号输入控制，但网络发展的逻辑及其在疾病中的解开尚不清楚。在发育过程中，膜系信号配体神经调节蛋白（Nrg） 1在心内膜中表达，对心室形态发生至关重要。在成人中，Nrg1可以防止心力衰竭，并可以诱导心肌细胞分裂。目的：通过对Nrg1无基因和半胚突变小鼠的分析，了解Nrg1在心脏发育中的作用。方法和结果：Nrg1突变体的腔室结构域被正确指定，但腔室限制性基因Hand1和Cited1未能被激活。室GRN随后随个体基因衰变，表现出与已知模式边界无关的衰变模式。小梁和非小梁心肌均受影响。网络消亡是时空动态的，最敏感的区域是左心室中央部分，在那里GRN完全崩溃。其他区域部分受分级敏感性影响。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。我们监测了胚胎中的心脏pErk1/2，发现突变体的表达依赖于nrg1，其水平与心脏GRN敏感性相关。结论：心室GRN从根本上是不稳定的，依赖于心外信号。Nrg1- erbb1 /4- erk1 /2信号通路对小梁和非小梁心肌中GRN元素的维持至关重要，挑战了我们对Nrg1功能的理解。Nrg1减少诱导的转录衰减模式提示心脏转录调节和疾病功能障碍的新机制，可能将生物力学反馈与生长和分化的分子途径联系起来。（Circ Res. 2010;107:715-727.）
Rationale: 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.Objective: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice.Methods and Results: 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.Conclusions: 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. (Circ Res. 2010;107:715-727.)