title: Neuregulin 1 sustains the gene regulatory network in both trabecular and nontrabecular myocardium.
abstract: 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.
authors.affiliation: Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St, Darlinghurst 2010, Australia.
authors.forename: Donna
authors.initials: D
authors.lastname: Lai
authors.forename: Xifu
authors.initials: X
authors.lastname: Liu
authors.forename: Ariel
authors.initials: A
authors.lastname: Forrai
authors.forename: Orit
authors.initials: O
authors.lastname: Wolstein
authors.forename: Jan
authors.initials: J
authors.lastname: Michalicek
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Ahmed
authors.forename: Alistair N
authors.initials: AN
authors.lastname: Garratt
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.forename: Mingdong
authors.initials: M
authors.lastname: Zhou
authors.forename: Lynne
authors.initials: L
authors.lastname: Hartley
authors.forename: Lorraine
authors.initials: L
authors.lastname: Robb
authors.forename: Michael P
authors.initials: MP
authors.lastname: Feneley
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
mesh_terms: 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
chemical_list: D020890:Neuregulin-1; C490581:Nrg1 protein, mouse