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Molecular and Cellular Biology, April 2009, p. 2205-2218, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01923-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Physical Interaction between TBX5 and MEF2C Is Required for Early Heart Development{triangledown} ,{dagger}

Tushar K. Ghosh,1 Fei Fei Song,1 Elizabeth A. Packham,1 Sarah Buxton,1 Thelma E. Robinson,1 Jonathan Ronksley,1 Tim Self,2 Andrew J. Bonser,1 and J. David Brook1*

Institute of Genetics, School of Biology,1 Institute of Cell Signalling, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom2

Received 19 December 2008/ Returned for modification 27 January 2009/ Accepted 31 January 2009

TBX5 is a transcription factor which plays important roles in the development of the heart and upper limbs. Mutations in this gene produce the inherited disorder Holt-Oram syndrome. Here, we report a physical interaction between TBX5 and MEF2C leading to a synergistic activation of the {alpha}-cardiac myosin heavy chain (MYH6). Mutants of TBX5, TBX5G80R, and TBX5R279X that produce severe cardiac phenotypes impair the synergy. Using fluorescence resonance energy transfer, we demonstrate the interaction of TBX5 and MEF2C in living cells. We also show that they physically associate through their DNA-binding domains to form a complex on the MYH6 promoter. Morpholino-mediated knockdowns of Tbx5 and Mef2c in zebrafish suggest that the genetic interaction of these proteins is not only required for MYH6 expression but also essential for the early stages of heart development and survival. This is the first report of a functional interaction between a T-box protein and a MADS box factor that may be crucial in cardiomyocyte differentiation.

* Corresponding author. Mailing address: Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. Phone: 44 (0)115 8230314. Fax: 44 (0)115 8230313. E-mail: David.Brook{at}nottingham.ac.uk

{triangledown} Published ahead of print on 9 February 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2009, p. 2205-2218, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01923-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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