Published online before print January 18, 2007, doi: 10.1161/01.RES.0000258019.74591.b3
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Submitted on September 21, 2006
Revised on December 21, 2006
Accepted on January 4, 2007
Molecular Pathway for the Localized Formation of the Sinoatrial Node
Mathilda T. M. Mommersteeg ;
From the Center for Heart Failure Research (M.T.M.M., W.M.H.H., C.d.G.-d.V., C.W., D.E.W.C., A.F.M.M., V.M.C.), Academic Medical Center, Amsterdam, The Netherlands; the Victor Chang Cardiac Research Institute (O.W.J.P., R.P.H.), Darlinghurst, Australia; the Faculties of Life Sciences and Medicine (R.P.H.), University of New South Wales, Kensington, Australia; Department of Genetics and Development (V.E.P.), College of Physicians and Surgeons of Columbia University, New York; and the Division of Basic Medical Sciences (N.A.B.), St. George’s, University of London, UK.
* To whom correspondence should be addressed. E-mail: v.m.christoffels{at}amc.uva.nl.
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 sinoatrial junction, indicating that Pitx2c functions within the left/right pathway to suppress a default program for sinoatrial 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.
Key words: heart development • sinus node • sinoatrial node • Nkx2-5 • Pitx2c • Tbx3 • Cx40 • transgenic mice
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