title: Physical interaction between TBX5 and MEF2C is required for early heart development.
abstract: 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.
authors.affiliation: Institute of Genetics, School of Biology, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Ghosh
authors.forename: Fei Fei
authors.initials: FF
authors.lastname: Song
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Packham
authors.forename: Sarah
authors.initials: S
authors.lastname: Buxton
authors.forename: Thelma E
authors.initials: TE
authors.lastname: Robinson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ronksley
authors.forename: Tim
authors.initials: T
authors.lastname: Self
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bonser
authors.forename: J David
authors.initials: JD
authors.lastname: Brook
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics*; D002460:Cell Line; D004625:Embryo, Nonmammalian; D006321:Heart / Q000254:growth & development*; D006801:Humans; D020125:Mutation, Missense; D018006:Myogenic Regulatory Factors / Q000378:metabolism* / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D015027:Zebrafish
chemical_list: C094239:MYH6 protein, human; D018006:Myogenic Regulatory Factors; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains