title: Molecular pathway for the localized formation of the sinoatrial node.
abstract: The sinoatrial node, which resides at the junction of the right atrium and the superior caval vein, contains specialized myocardial cells that initiate the heart beat. Despite this fundamental role in heart function, the embryonic origin and mechanisms of localized formation of the sinoatrial node have not been defined. Here we show that subsequent to the formation of the Nkx2-5-positive heart tube, cells bordering the inflow tract of the heart tube give rise to the Nkx2-5-negative myocardial cells of the sinoatrial node and the sinus horns. Using genetic models, we show that as the myocardium of the heart tube matures, Nkx2-5 suppresses pacemaker channel gene Hcn4 and T-box transcription factor gene Tbx3, thereby enforcing a progressive confinement of their expression to the forming Nkx2-5-negative sinoatrial node and sinus horns. Thus, Nkx2-5 is essential for establishing a gene expression border between the atrium and sinoatrial node. Tbx3 was found to suppress chamber differentiation, providing an additional mechanism by which the Tbx3-positive sinoatrial node is shielded from differentiating into atrial myocardium. Pitx2c-deficient fetuses form sinoatrial nodes with indistinguishable molecular signatures at both the right and left sinuatrial junction, indicating that Pitx2c functions within the left/right pathway to suppress a default program for sinuatrial node formation on the left. Our molecular pathway provides a mechanism for how pacemaker activity becomes progressively relegated to the most recently added components of the venous pole of the heart and, ultimately, to the junction of the right atrium and superior caval vein.
authors.affiliation: Center for Heart Failure Research, Academic Medical Centre, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Mathilda T M
authors.initials: MT
authors.lastname: Mommersteeg
authors.forename: Willem M H
authors.initials: WM
authors.lastname: Hoogaars
authors.forename: Owen W J
authors.initials: OW
authors.lastname: Prall
authors.forename: Corrie
authors.initials: C
authors.lastname: de Gier-de Vries
authors.forename: Cornelia
authors.initials: C
authors.lastname: Wiese
authors.forename: Danielle E W
authors.initials: DE
authors.lastname: Clout
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Papaioannou
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor; D015415:Biomarkers; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D024722:Cardiac Myosins / Q000096:biosynthesis / Q000235:genetics; D017630:Connexins / Q000096:biosynthesis / Q000235:genetics; D054815:Cyclic Nucleotide-Gated Cation Channels; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D017930:Genes, Reporter; D006325:Heart Atria / Q000196:embryology*; D006352:Heart Ventricles / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D021621:Imaging, Three-Dimensional; D017403:In Situ Hybridization; D007473:Ion Channels / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D018994:Myosin Light Chains / Q000096:biosynthesis / Q000235:genetics; D020098:Natriuretic Peptide, C-Type / Q000096:biosynthesis / Q000235:genetics; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012849:Sinoatrial Node / Q000166:cytology / Q000196:embryology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019210:Troponin I / Q000096:biosynthesis / Q000235:genetics; D000097003:Gap Junction alpha-5 Protein; D000097577:Homeobox Protein PITX2
chemical_list: D009320:Atrial Natriuretic Factor; D015415:Biomarkers; D024722:Cardiac Myosins; D017630:Connexins; D054815:Cyclic Nucleotide-Gated Cation Channels; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D018994:Myosin Light Chains; D020098:Natriuretic Peptide, C-Type; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D019210:Troponin I; D000097003:Gap Junction alpha-5 Protein; D000097577:Homeobox Protein PITX2; C484469:Nkx2-5 protein, mouse; C431578:Nppa protein, mouse; C106884:TBX3 protein, human; C491460:Tbx3 protein, mouse; C107184:myosin light chain 2