title: Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart.
abstract: OBJECTIVE
  Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart.
  
  
  RESULTS
  In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis.
  
  
  CONCLUSIONS
  Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasis.
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Metrich
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: April
authors.initials: A
authors.lastname: Bezdek Pomey
authors.affiliation: Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Berthonneche
authors.affiliation: Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sarre
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Nemir
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland thierry.pedrazzini@chuv.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D006706:Homeostasis; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051881:Receptor, Notch1 / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D060449:Wnt Signaling Pathway
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: Cardiac hypertrophy; Cardiomyocyte differentiation; Jagged1-intracelullar domain; Notch signalling