title: Sequential Notch activation regulates ventricular chamber development.
abstract: Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4-Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies.
authors.affiliation: Intercellular Signalling in Cardiovascular Development &Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Gaetano
authors.initials: G
authors.lastname: D'Amato
authors.affiliation: Intercellular Signalling in Cardiovascular Development &Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Luxán
authors.affiliation: Intercellular Signalling in Cardiovascular Development &Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: del Monte-Nieto
authors.affiliation: Intercellular Signalling in Cardiovascular Development &Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martínez-Poveda
authors.affiliation: Bioinformatics Unit, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Torroja
authors.affiliation: Bioinformatics Unit, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Wencke
authors.initials: W
authors.lastname: Walter
authors.affiliation: Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Bochter
authors.affiliation: Molecular Genetics of Angiogenesis Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Rui
authors.initials: R
authors.lastname: Benedito
authors.affiliation: Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Cole
authors.affiliation: Bioinformatics Unit, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.affiliation: Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Akiyoshi
authors.identifier: http://orcid.org/0000-0001-5574-5470
authors.initials: A
authors.lastname: Uemura
authors.affiliation: Cardiovascular Imaging Laboratory, CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.|Instituto de Investigación Sanitaria Hospital La Princesa, 28006 Madrid, Spain.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: Intercellular Signalling in Cardiovascular Development &Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: de la Pompa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005964:Glucosyltransferases; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism*; D006602:Hexosyltransferases / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D038081:Organogenesis / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051880:Receptors, Notch; D005964:Glucosyltransferases; D006602:Hexosyltransferases; C106516:MFNG protein, human