title: Irx3 is required for postnatal maturation of the mouse ventricular conduction system.
abstract: The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43. However, it is unknown whether other factors contribute to the conduction defects observed in Irx3 knockout (Irx3(-/-)) mice. In this study, we show that during the early postnatal period, Irx3(-/-) mice develop morphological defects in the VCS which are temporally dissociated from changes in gap junction expression. These morphological defects were accompanied with progressive changes in the cardiac electrocardiogram including right bundle branch block. Hypoplastic VCS was not associated with increased apoptosis of VCS cardiomyocytes but with a lack of recruitment and maturation of ventricular cardiomyocytes into the VCS. Computational analysis followed by functional verification revealed that Irx3 promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx5. Altogether, these results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx3 is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx5 and Nkx2.5.
authors.affiliation: Program in Developmental &Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Kyoung-Han
authors.initials: KH
authors.lastname: Kim
authors.affiliation: The Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3E2, Canada.|Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosen
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.|Centre Hospitalier Universitaire de Québec Research Center and Faculty of Medicine, Laval University, Quebec City, QC G1V 4G2, Canada.
authors.forename: Samer M I
authors.initials: SM
authors.lastname: Hussein
authors.affiliation: Program in Developmental &Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Vijitha
authors.initials: V
authors.lastname: Puviindran
authors.affiliation: The Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3E2, Canada.|Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Korogyi
authors.affiliation: The Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3E2, Canada.|Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Carmelina
authors.initials: C
authors.lastname: Chiarello
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.|Institute of Medical Science and Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.affiliation: Program in Developmental &Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.affiliation: The Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3E2, Canada.|Departments of Physiology and Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.|Peter Munk Cardiac Centre and Division of Cardiology, University Health Network, Toronto ON.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism; D000075224:Cardiac Conduction System Disease; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004562:Electrocardiography; D015870:Gene Expression; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000254:growth & development* / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D011485:Protein Binding; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000097003:Gap Junction alpha-5 Protein; C501599:Irx3 protein, mouse; C484469:Nkx2-5 protein, mouse; C103172:T-box transcription factor 5