The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription factors 
that are essential for differentiation of all muscle lineages but their 
mechanisms of action remain largely undefined. In mammals, the earliest site of 
MEF2 expression is the heart where the MEF2C isoform is detectable as early as 
embryonic day 7.5. Inactivation of the MEF2C gene causes cardiac developmental 
arrest and severe downregulation of a number of cardiac markers including atrial 
natriuretic factor (ANF). However, most of these promoters contain no or low 
affinity MEF2 binding sites and they are not significantly activated by any MEF2 
proteins in heterologous cells suggesting a dependence on a cardiac-enriched 
cofactor for MEF2 action. We provide evidence that MEF2 proteins are recruited 
to target promoters by the cell-specific GATA transcription factors, and that 
MEF2 potentiates the transcriptional activity of this family of 
tissue-restricted zinc finger proteins. Functional MEF2/GATA-4 synergy involves 
physical interaction between the MEF2 DNA-binding domain and the carboxy zinc 
finger of GATA-4 and requires the activation domains of both proteins. However, 
neither MEF2 binding sites nor MEF2 DNA binding capacity are required for 
transcriptional synergy. The results unravel a novel pathway for transcriptional 
regulation by MEF2 and provide a molecular paradigm for elucidating the 
mechanisms of action of MEF2 in muscle and non-muscle cells.