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Molecular pathway for the localized formation of the sinoatrial node.
- Source :
-
Circulation research [Circ Res] 2007 Feb 16; Vol. 100 (3), pp. 354-62. Date of Electronic Publication: 2007 Jan 18. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Atrial Natriuretic Factor
Biomarkers
Body Patterning genetics
Cardiac Myosins biosynthesis
Cardiac Myosins genetics
Connexins biosynthesis
Connexins genetics
Cyclic Nucleotide-Gated Cation Channels
Gene Expression Regulation, Developmental genetics
Genes, Reporter
Homeobox Protein Nkx-2.5
Homeodomain Proteins genetics
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Imaging, Three-Dimensional
In Situ Hybridization
Ion Channels genetics
Mice
Mice, Knockout
Mice, Transgenic
Myocardium metabolism
Myosin Light Chains biosynthesis
Myosin Light Chains genetics
Natriuretic Peptide, C-Type biosynthesis
Natriuretic Peptide, C-Type genetics
Protein Precursors biosynthesis
Protein Precursors genetics
Recombinant Fusion Proteins physiology
Sinoatrial Node cytology
T-Box Domain Proteins biosynthesis
T-Box Domain Proteins genetics
Transcription Factors deficiency
Transcription Factors genetics
Troponin I biosynthesis
Troponin I genetics
Gap Junction alpha-5 Protein
Homeobox Protein PITX2
Body Patterning physiology
Gene Expression Regulation, Developmental physiology
Heart Atria embryology
Heart Ventricles embryology
Homeodomain Proteins physiology
Ion Channels biosynthesis
Sinoatrial Node embryology
T-Box Domain Proteins physiology
Transcription Factors physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 100
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 17234970
- Full Text :
- https://doi.org/10.1161/01.RES.0000258019.74591.b3