Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 19, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn049
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MSX1 AND MSX2 ARE FUNCTIONAL INTERACTING PARTNERS OF T-BOX FACTORS IN THE REGULATION OF CONNEXIN43
Heart Failure Research Centre, Academic Medical Centre, University of Amsterdam
Address correspondence to: Phil Barnett, Department of Anatomy and Embryology, AMC, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands Tel. +31-205667821, Fax: +31-206976177, Email: p.barnett{at}amc.uva.nl
Aims: The 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 a 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, like 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 on the presence of Tbx3.
Conclusions: Msx1 and Msx2 can function in concert with the T-box proteins to suppress Cx43 and other working myocardial genes.
Time for primary review: 21 days
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