Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development

Meenakshi Maitra, Marie K. Schluterman, Haley A. Nichols, James A. Richardson, Cecilia W. Lo, Deepak Srivastava, Vidu Garg

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

Congenital heart disease is the most common type of birth defect with an incidence of 1%. Previously, we described a point mutation in GATA4 that segregated with cardiac defects in a family with autosomal dominant disease. The mutation (G296S) exhibited biochemical deficits and disrupted a novel interaction between Gata4 and Tbx5. To determine if Gata4 and Tbx5 genetically interact in vivo, we generated mice heterozygous for both alleles. We found that nearly 100% of mice heterozygous for Gata4 and Tbx5 were embryonic or neonatal lethal and had complete atrioventricular (AV) septal defects with a single AV valve and myocardial thinning. Consistent with this phenotype, Gata4 and Tbx5 are co-expressed in the developing endocardial cushions and myocardium. In mutant embryos, cardiomyocyte proliferation deficits were identified compatible with the myocardial hypoplasia. Similar to Gata4, Gata6 and Tbx5 are co-expressed in the embryonic heart, and the transcription factors synergistically activate the atrial natiuretic factor promoter. We demonstrate a genetic interaction between Gata6 and Tbx5 with an incompletely penetrant phenotype of neonatal lethality and thin myocardium. Gene expression analyses were performed on both sets of compound heterozygotes and demonstrated downregulation of α-myosin heavy chain only in Gata4/Tbx5 heterozygotes. These findings highlight the unique genetic interactions of Gata4 and Gata6 with Tbx5 for normal cardiac morphogenesis in vivo.

Original languageEnglish (US)
Pages (from-to)368-377
Number of pages10
JournalDevelopmental Biology
Volume326
Issue number2
DOIs
StatePublished - Feb 15 2009

Keywords

  • Cardiac development
  • Congenital heart defects
  • Gata4
  • Gata6
  • Tbx5
  • Transcription factor

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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    Maitra, M., Schluterman, M. K., Nichols, H. A., Richardson, J. A., Lo, C. W., Srivastava, D., & Garg, V. (2009). Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Developmental Biology, 326(2), 368-377. https://doi.org/10.1016/j.ydbio.2008.11.004