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Neuregulin 1 sustains the gene regulatory network in both trabecular and nontrabecular myocardium

Item Type:Article
Title:Neuregulin 1 sustains the gene regulatory network in both trabecular and nontrabecular myocardium
Creators Name:Lai, D. and Forrai, A. and Liu, X. and Wolstein, O. and Michalicek, J. and Ahmed, I. and Garratt, A.N. and Birchmeier, C. and Zhou, M. and Hartley, L. and Robb, L. and Feneley, M.P. and Fatkin, D. and Harvey, R.P.
Abstract: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.
Keywords:Neuregulin 1, Cardiac Gene Regulation, Heart Development, Cardiac Gene Regulatory Network, Animals, Cattle, Mice
Source:Circulation Research
ISSN:0009-7330
Publisher:American Heart Association (U.S.A.)
Volume:107
Number:6
Page Range:715-727
Date:17 September 2010
Official Publication:https://doi.org/10.1161/CIRCRESAHA.110.218693
PubMed:View item in PubMed

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