GATA4 is a dosage-sensitive regulator of cardiac morphogenesis

William T. Pu, Takahiro Ishiwata, Amy L. Juraszek, Qing Ma, Seigo Izumo

Research output: Contribution to journalArticlepeer-review

196 Scopus citations


Normal heart development is orchestrated by a set of highly conserved transcription factors that includes GATA4, Nkx2-5, and Tbx5. Heterozygous mutation of each of these genes causes congenital heart disease in humans. In mouse models, haploinsufficiency for Nkx2-5 or Tbx5 resulted in an increased incidence of structural heart disease, confirming that normal heart development is sensitive to small changes in expression levels of Nkx2-5 and Tbx5. However, mice haploinsufficient for GATA4 have not been reported to have cardiac abnormalities. We generated two new GATA4 alleles, GATA4H and GATA4flox. GATA4flox/flox embryos expressed 50% less GATA4 protein in the heart and survived normally. In contrast, GATA4H/H embryos expressed 70% less GATA4 protein in the heart and died between days 13.5 and 16.5 of gestation. These embryos had common atrioventricular canal (CAVC), double outlet right ventricle (DORV), hypoplastic ventricular myocardium, and normal coronary vasculature. Myocardial hypoplasia was associated with diminished cardiomyocyte proliferation. Hemodynamic measurements demonstrated that these embryos had normal systolic function, severe diastolic dysfunction, and atrioventricular regurgitation. Surprisingly, expression levels of the putative GATA4 target genes ANF, BNP, MEF2C, Nkx2-5, cyclin D2, and BMP4 were unchanged in mutant hearts, suggesting that GATA4 is not a dose-limiting regulator of the expression of these genes during later stages of embryonic cardiac development. These data demonstrate that multiple aspects of embryonic cardiac morphogenesis and function are exquisitely sensitive to small changes in GATA4 expression levels.

Original languageEnglish (US)
Pages (from-to)235-244
Number of pages10
JournalDevelopmental Biology
Issue number1
StatePublished - Nov 1 2004


  • Cardiac morphogenesis
  • GATA4
  • Heart

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


Dive into the research topics of 'GATA4 is a dosage-sensitive regulator of cardiac morphogenesis'. Together they form a unique fingerprint.

Cite this