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The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors.

The tissue-restricted GATA-4 transcription factor and Nkx2-5 homeodomain protein are two early markers of precardiac cells. Both are essential for heart formation, but neither can initiate cardiogenesis. Overexpression of GATA-4 or Nkx2-5 enhances cardiac development in committed precursors, suggesting each interacts with a cardiac cofactor. We tested whether GATA-4 and Nkx2-5 are cofactors for each other by using transcription and binding assays with the cardiac atrial natriuretic factor (ANF) promoter_the only known target for Nkx2-5. Co-expression of GATA-4 and Nkx2-5 resulted in synergistic activation of the ANF promoter in heterologous cells. The synergy involves physical Nkx2-5-GATA-4 interaction, seen in vitro and in vivo, which maps to the C-terminal zinc finger of GATA-4 and a C-terminus extension; similarly, a C-terminally extended homeodomain of Nkx2-5 is required for GATA-4 binding. Structure/function studies suggest that binding of GATA-4 to the C-terminus autorepressive domain of Nkx2-5 may induce a conformational change that unmasks Nkx2-5 activation domains. GATA-6 cannot substitute for GATA-4 for interaction with Nkx2-5. This interaction may impart functional specificity to GATA factors and provide cooperative crosstalk between two pathways critical for early cardiogenesis. Given the co-expression of GATA proteins and NK2 class members in other tissues, the GATA/Nkx partnership may represent a paradigm for transcription factor interaction during organogenesis.

Pubmed ID: 9312027


  • Durocher D
  • Charron F
  • Warren R
  • Schwartz RJ
  • Nemer M


The EMBO journal

Publication Data

September 15, 1997

Associated Grants

  • Agency: PHS HHS, Id: R0150422

Mesh Terms

  • Animals
  • Atrial Natriuretic Factor
  • Base Sequence
  • Caenorhabditis elegans
  • Cell Line
  • Conserved Sequence
  • DNA-Binding Proteins
  • Drosophila
  • GATA4 Transcription Factor
  • HeLa Cells
  • Heart
  • Homeodomain Proteins
  • Humans
  • Molecular Sequence Data
  • Myocardium
  • Promoter Regions, Genetic
  • Recombinant Fusion Proteins
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Vertebrates
  • Xenopus Proteins