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A threshold of GATA4 and GATA6 expression is required for cardiovascular development
Open accessAbstract
The zinc-finger transcription factors GATA4 and GATA6 play critical roles in embryonic development. Mouse embryos lacking GATA4 die at embryonic day (E) 8.5 because of failure of ventral foregut closure and cardiac bifida, whereas GATA6 is essential for development of the visceral endoderm. Although mice that are heterozygous for either a GATA4 or GATA6 null allele are normal, we show that compound heterozygosity of GATA4 and GATA6 results in embryonic lethality by E13.5 accompanied by a spectrum of cardiovascular defects, including thin-walled myocardium, ventricular and aortopulmonary septal defects, and abnormal smooth muscle development. Myocardial hypoplasia in GATA4/GATA6 double heterozygous mutant embryos is associated with reduced proliferation of cardiomyocytes, diminished expression of the myogenic transcription factor MEF2C (myocyte enhancer factor 2C), and down-regulation of β-myosin heavy chain expression, a key determinant of cardiac contractility. These findings reveal a threshold of GATA4 and GATA6 activity that is required for gene expression in the developing cardiovascular system and underscore the potential of recessive mutations to perturb the delicate regulation of cardiovascular development.
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Cited by
Xin, M., Small, E. M., Sutherland, L. B., Qi, X., McAnally, J., Plato, C. F., Richardson, J. A., Bassel-Duby, R., & Olson, E. N. (2009) · Genes & Development · doi:10.1101/gad.1842409 · Cited by 649
Self-citationMontgomery, R. L., Hsieh, J., Barbosa, A. C., Richardson, J. A., & Olson, E. N. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902750106 · Cited by 306
Self-citationInduction of Pluripotency in Mouse Somatic Cells with Lineage Specifiers
Shu, J., Wu, C., Wu, Y., Li, Z., Shao, S., Zhao, W., Tang, X., Yang, H., Shen, L., Zuo, X., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.001 · Cited by 305
Yuan, X., Song, M., Devine, P., Bruneau, B. G., Scott, I. C., & Wilson, M. D. (2018) · Nature Communications · doi:10.1038/s41467-018-07451-z · Cited by 51
Cardiac differentiation roadmap for analysis of plasticity and balanced lineage commitment
Snabel, R. R., Cofiño-Fabrés, C., Baltissen, M., Schwach, V., Passier, R., & Veenstra, G. J. C. (2025) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102422 · Cited by 10
Metadata
- Authors
- Xin, M., Davis, C. A., Molkentin, J. D., Lien, C.-L., Duncan, S. A., Richardson, J. A., & Olson, E. N.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2006-07-25
- Volume
- 103
- Issue
- 30
- Pages
- 11189-11194
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2126352334
- Cited by
- 198
- References
- 0
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- green
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- Xin, M., Davis, C. A., Molkentin, J. D., Lien, C.-L., Duncan, S. A., Richardson, J. A., & Olson, E. N. (2006). A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0604604103
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