title: T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells.
abstract: OBJECTIVE
  Treatment of disorders of the sinus node or the atrioventricular node requires insights into the molecular mechanisms of development and homoeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogramme terminally differentiated working cardiomyocytes into pacemaker cells.
  
  
  RESULTS
  TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice using tamoxifen. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na(+) channel (Na(V)1.5; I(Na)), and inwardly rectifying K(+) ion channels (K(ir) genes; I(K1)). Concordantly, we observed conduction slowing in these hearts and reductions in I(Na) and I(K1) in cardiomyocytes isolated from these hearts. The reduction in I(K1) resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current I(f) was observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes.
  
  
  CONCLUSIONS
  TBX3 reprogrammes terminally differentiated working cardiomyocytes and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce I(K1) density to enable diastolic depolarization are promising TBX3 characteristics that may facilitate biological pacemaker formation strategies.
authors.affiliation: Heart Failure Research Center,  Academic Medical Center, University of Amsterdam, Meibergdreef 15, Room L2-108, 1105 AZ, Amsterdam,  The Netherlands.
authors.forename: Martijn L
authors.initials: ML
authors.lastname: Bakker
authors.forename: Gerard J J
authors.initials: GJ
authors.lastname: Boink
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Boukens
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: Malou
authors.initials: M
authors.lastname: van den Boogaard
authors.forename: A Denise
authors.initials: AD
authors.lastname: den Haan
authors.forename: Willem M H
authors.initials: WM
authors.lastname: Hoogaars
authors.forename: Henk P
authors.initials: HP
authors.lastname: Buermans
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Jurgen
authors.initials: J
authors.lastname: Seppen
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000235:genetics*; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse