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

Open Access
Publisher Website
Google Scholar
Abstract
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.