Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

Significance Dominant GATA4 mutations cause congenital heart defects in humans, but the mechanistic basis whereby Gata4 haploinsufficiency causes disease is unknown. We demonstrate that Gata4 is required in a subset of cardiac progenitor cells called the “second heart field” for cardiac septation. Furthermore, we identified two distinct pathways downstream of Gata4 , phosphatase and tensin homolog ( Pten )-modulated cell-cycle transition and Hedgehog signaling, which appear to act independently. Restoration of either Pten -mediated cell-cycle transition or Hedgehog signaling restored cardiac septation in Gata4 -mutant mice, suggesting that defects in both pathways are required for disease causation. This work generates a working model for understanding the molecular basis of human congenital heart disease caused by dominant transcription factor mutations.