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Cardiovascular Research Advance Access originally published online on February 19, 2008
Cardiovascular Research 2008 78(3):485-493; doi:10.1093/cvr/cvn049
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43

Kees-Jan Boogerd, L.Y. Elaine Wong, Vincent M. Christoffels, Meinke Klarenbeek, Jan M. Ruijter, Antoon F.M. Moorman and Phil Barnett*

Department of Anatomy and Embryology, Heart Failure Research Centre, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands

* Corresponding author. Tel: +31 20 566 7821; fax: +31 20 697 6177. E-mail address: p.barnett{at}amc.uva.nl

Aims: T-box factors Tbx2 and Tbx3 play key roles in the development of the cardiac conduction system, atrioventricular canal, and outflow tract of the heart. They regulate the gap-junction-encoding gene Connexin43 (Cx43) and other genes critical for heart development and function. Discovering protein partners of Tbx2 and Tbx3 will shed light on the mechanisms by which these factors regulate these gene programs.

Methods and results: Employing an yeast 2-hybrid screen and subsequent in vitro pull-down experiments we demonstrate that muscle segment homeobox genes Msx1 and Msx2 are able to bind the cardiac T-box proteins Tbx2, Tbx3, and Tbx5. This interaction, as that of the related Nkx2.5 protein, is supported by the T-box and homeodomain alone. Overlapping spatiotemporal expression patterns of Msx1 and Msx2 together with the T-box genes during cardiac development in mouse and chicken underscore the biological significance of this interaction. We demonstrate that Msx proteins together with Tbx2 and Tbx3 suppress Cx43 promoter activity and down regulate Cx43 gene activity in a rat heart-derived cell line. Using chromatin immunoprecipitation analysis we demonstrate that Msx1 can bind the Cx43 promoter at a conserved binding site located in close proximity to a previously defined T-box binding site, and that the activity of Msx proteins on this promoter appears dependent in the presence of Tbx3.

Conclusion: Msx1 and Msx2 can function in concert with the T-box proteins to suppress Cx43 and other working myocardial genes.

KEYWORDS T-box transcription factor; Heart development; Tbx2; Tbx3; Msx1; Msx2; Connexin43; Atrioventricular canal; Working myocardium; Cardiac conduction system; Mouse; Chicken

Time for primary review: 21 days


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