Published online before print May 7, 2009, doi: 10.1161/CIRCRESAHA.108.192450
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Submitted on December 10, 2008
Revised on April 20, 2009
Accepted on April 23, 2009
The Tbx2+ Primary Myocardium of the Atrioventricular Canal Forms the Atrioventricular Node and the Base of the Left Ventricle
Wim T.J. Aanhaanen ;
From the Heart Failure Research Center (W.T.J.A., J.F.B., M.S.R., V.W., C.d.G.-d.V., A.F.M.M., V.M.C.), Academic Medical Center, University of Amsterdam, The Netherlands; Division of Basic Medical Sciences (N.A.B., J.N.D.), St George's University of London, United Kingdom; Institut für Molekularbiologie (J.N., R.A., A.K.), Medizinische Hochschule Hannover, Germany; and Department of Experimental Biology (J.N.D.), Faculty of Experimental Sciences, University of Jaén, Spain.
* To whom correspondence should be addressed. E-mail: v.m.christoffels{at}amc.uva.nl.
The primary myocardium of the embryonic heart, including the atrioventricular canal and outflow tract, is essential for septation and valve formation. In the chamber-forming heart, the expression of the T-box transcription factor Tbx2 is restricted to the primary myocardium. To gain insight into the cellular contributions of the Tbx2+ primary myocardium to the components of the definitive heart, genetic lineage tracing was performed using a novel Tbx2Cre allele. These analyses revealed that progeny of Tbx2+ cells provide an unexpectedly large contribution to the Tbx2-negative ventricles. Contrary to common assumption, we found that the embryonic left ventricle only forms the left part of the definitive ventricular septum and the apex. The atrioventricular node, but not the atrioventricular bundle, was found to derive from Tbx2+ cells. The Tbx2+ outflow tract formed the right ventricle and right part of the ventricular septum. In Tbx2-deficient embryos, the left-sided atrioventricular canal was found to prematurely differentiate to chamber myocardium and to proliferate at increased rates similar to those of chamber myocardium. As a result, the atrioventricular junction and base of the left ventricle were malformed. Together, these observations indicate that Tbx2 temporally suppresses differentiation and proliferation of primary myocardial cells. A subset of these Tbx2Cre-marked cells switch off expression of Tbx2, which allows them to differentiate into chamber myocardium, to initiate proliferation, and to provide a large contribution to the ventricles. These findings imply that errors in the development of the early atrioventricular canal may affect a much larger region than previously anticipated, including the ventricular base.
Key words: atrioventricular canal • lineage • fate • patterning • transgenic • Cre
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