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


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.
Lai
Donna
D
Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St, Darlinghurst 2010, Australia.
Liu
Xifu
X
Forrai
Ariel
A
Wolstein
Orit
O
Michalicek
Jan
J
Ahmed
Ishtiaq
I
Garratt
Alistair N
AN
Birchmeier
Carmen
C
Zhou
Mingdong
M
Hartley
Lynne
L
Robb
Lorraine
L
Feneley
Michael P
MP
Fatkin
Diane
D
Harvey
Richard P
RP
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D053263:Gene Regulatory Networks / Q000502:physiology*; D006321:Heart / Q000196:embryology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D020890:Neuregulin-1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D020890:Neuregulin-1; C490581:Nrg1 protein, mouse