This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/3/388    most recent CIRCRESAHA.108.187062v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wiese, C. Articles by Christoffels, V. M. Search for Related Content PubMed PubMed Citation Articles by Wiese, C. Articles by Christoffels, V. M. Related Collections Structure Animal models of human disease Developmental biology Gene expression Genetically altered mice Myogenesis Cardiac development Related Article

(Circulation Research. 2009;104:388.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Formation of the Sinus Node Head and Differentiation of Sinus Node Myocardium Are Independently Regulated by Tbx18 and Tbx3

Cornelia Wiese^*, Thomas Grieskamp^*, Rannar Airik, Mathilda T.M. Mommersteeg, Ajmal Gardiwal, Corrie de Gier-de Vries, Karin Schuster-Gossler, Antoon F.M. Moorman, Andreas Kispert^*, Vincent M. Christoffels^*

From the Center for Heart Failure Research (C.W., M.T.M.M., C.d.G.-d.V., A.F.M.M., V.M.C.), Academic Medical Centre, Amsterdam, The Netherlands; and Institute for Molecular Biology (T.G., R.A., K.S.-G., A.K.) and Department of Cardiology and Angiology (A.G.), Medizinische Hochschule Hannover, Germany.

Correspondence to Vincent M. Christoffels, Center for Heart Failure Research, Academic Medical Centre, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. E-mail v.m.christoffels{at}amc.uva.nl

The sinus node (or sinoatrial node [SAN]), the pacemaker of the heart, is a functionally and structurally heterogeneous tissue, which consists of a large "head" within the right caval vein myocardium and a "tail" along the terminal crest. Here, we investigated its cellular origin and mechanism of formation. Using genetic lineage analysis and explant assays, we identified T-box transcription factor Tbx18-expressing mesenchymal progenitors in the inflow tract region that differentiate into pacemaker myocardium to form the SAN. We found that the head and tail represent separate regulatory domains expressing distinctive gene programs. Tbx18 is required to establish the large head structure, as seen by the existence of a very small but still functional tail piece in Tbx18-deficient fetuses. In contrast, Tbx3-deficient embryos formed a morphologically normal SAN, which, however, aberrantly expressed Cx40 and other atrial genes, demonstrating that Tbx3 controls differentiation of SAN head and tail cardiomyocytes but also demonstrating that Tbx3 is not required for the formation of the SAN structure. Our data establish a functional order for Tbx18 and Tbx3 in SAN formation, in which Tbx18 controls the formation of the SAN head from mesenchymal precursors, on which Tbx3 subsequently imposes the pacemaker gene program.

Key Words: heart development • progenitors • Hcn4 • Cx43 • transgenic mice

Related Article:

Setting the Pace: Tbx3 and Tbx18 in Cardiac Conduction System Development

Elizabeth M. McNally and Eric C. Svensson
Circ. Res. 2009 104: 285-287. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				C. J. Hatcher and C. T. Basson Specification of the Cardiac Conduction System by Transcription Factors Circ. Res., September 25, 2009; 105(7): 620 - 630. [Abstract] [Full Text] [PDF]