title: Erbb2 is required for cardiac atrial electrical activity during development.
abstract: The heart is the first organ required to function during embryonic development and is absolutely necessary for embryo survival. Cardiac activity is dependent on both the sinoatrial node (SAN), which is the pacemaker of heart's electrical activity, and the cardiac conduction system which transduces the electrical signal though the heart tissue, leading to heart muscle contractions. Defects in the development of cardiac electrical function may lead to severe heart disorders. The Erbb2 (Epidermal Growth Factor Receptor 2) gene encodes a member of the EGF receptor family of receptor tyrosine kinases. The Erbb2 receptor lacks ligand-binding activity but forms heterodimers with other EGF receptors, stabilising their ligand binding and enhancing kinase-mediated activation of downstream signalling pathways. Erbb2 is absolutely necessary in normal embryonic development and homozygous mouse knock-out Erbb2 embryos die at embryonic day (E)10.5 due to severe cardiac defects. We have isolated a mouse line, l11Jus8, from a random chemical mutagenesis screen, which carries a hypomorphic missense mutation in the Erbb2 gene. Homozygous mutant embryos exhibit embryonic lethality by E12.5-13. The l11Jus8 mutants display cardiac haemorrhage and a failure of atrial function due to defects in atrial electrical signal propagation, leading to an atrial-specific conduction block, which does not affect ventricular conduction. The l11Jus8 mutant phenotype is distinct from those reported for Erbb2 knockout mouse mutants. Thus, the l11Jus8 mouse reveals a novel function of Erbb2 during atrial conduction system development, which when disrupted causes death at mid-gestation.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Tenin
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Clowes
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Wolton
authors.affiliation: Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, and Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Eliska
authors.initials: E
authors.lastname: Krejci
authors.affiliation: Syngenta Ltd, Jeallots Hill, United Kingdom.
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Wright
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Lovell
authors.affiliation: Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, and Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Sedmera
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hentges
mesh_terms: D000200:Action Potentials; D000818:Animals; D016275:Atrial Function; D006325:Heart Atria / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D006329:Heart Conduction System / Q000196:embryology / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse