title: Prokineticin receptor-1 signaling promotes Epicardial to Mesenchymal Transition during heart development.
abstract: The epicardium plays an essential role in coronary artery formation and myocardial development. However, signals controlling the developing epicardium and epicardial-mesenchymal transition (EMT) in the normal and diseased adult heart are studied less rigorously. Here we investigated the role of angiogenic hormone, prokineticin-2 and its receptor PKR1 in the epicardium of developing and adult heart. Genetic ablation of PKR1 in epicardium leads to partial embryonic and postnatal lethality with abnormal heart development. Cardiac developmental defects are manifested in the adult stage as ischemic cardiomyopathy with systolic dysfunction. We discovered that PKR1 regulates epicardial-mesenchymal transition (EMT) for epicardial-derived progenitor cell (EPDC), formation. This event affects at least three consequential steps during heart development: (i) EPDC and cardiomyocyte proliferation involved in thickening of an outer compact ventricular chamber wall, (ii) rhythmicity, (iii) formation of coronary circulation. In isolated embryonic EPDCs, overexpression or activation of PKR1 alters cell morphology and EMT markers via activating Akt signaling. Lack of PKR1 signal in epicardium leads to defective heart development and underlies the origin of congenital heart disease in adult mice. Our mice provide genetic models for congenital dysfunction of the heart and should facilitate studies of both pathogenesis and therapy of cardiac disorders in humans.
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Arora
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Boulberdaa
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Rehana
authors.initials: R
authors.lastname: Qureshi
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Verda
authors.initials: V
authors.lastname: Bitirim
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Gasser
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, UMR 7104 and INSERM Unité 964, Université de Strasbourg, Illkirch-Strasbourg, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, UMR 7104 and INSERM Unité 964, Université de Strasbourg, Illkirch-Strasbourg, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dolle
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Canan G
authors.initials: CG
authors.lastname: Nebigil
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D006321:Heart / Q000196:embryology*; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism*; D010496:Pericardium / Q000196:embryology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C525015:PKR1 protein, mouse; C486586:Prok2 protein, mouse; D043562:Receptors, G-Protein-Coupled