Development of heart valves requires Gata4 expression in endothelial-derived cells
Open accessAbstract
Cardiac malformations due to aberrant development of the atrioventricular(AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions,the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form the mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in the formation of portions of the atrial and ventricular septae, and the generation of thin, pliable valves. Gata4, which encodes a zinc finger transcription factor, is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in a decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling.
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EndMT is controlled by transcription factors including SNAI2, GATA4, and SOX9, activated in response to cues including TGFβ, WNT, and NOTCH.
“This transdifferentiation event is controlled by various transcription factors, like SNAI214, GATA415, and SOX916,17, which are activated in response to cues from neighbouring cell types, including the TGFβ superfamily9,10, WNT18, and NOTCH19,20.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [15]
Endocardial Gata4 is required for EndMT initiation.
“Endocardial Gata4 is required for EndMT initiation15”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [15]
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- Authors
- Rivera-Feliciano, J., Lee, K.-H., Kong, S. W., Rajagopal, S., Ma, Q., Springer, Z., Izumo, S., Tabin, C. J., & Pu, W. T.
- Affiliations
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Corresponding author
- Pu, William T.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2006-09-15
- Volume
- 133
- Issue
- 18
- Pages
- 3607-3618
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC2735081
- OpenAlex
- W1979437598
- Cited by
- 190
- References
- 42
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 8 · 2019: 13 · 2018: 20 · 2017: 9 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 15 · 2012: 13
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Heart, Lung, and Blood Institute (F31HL068295, 1 P01 HL074734, K08HL004387, P50HL074734, T32HL007572)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD0045499, R01HD045499)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- GATA4, atrioventricular valves, endocardial cushion, endothelial-to-mesenchymal transition, HER3, ERK signaling, congenital heart disease, heart valve development
- MeSH terms
- Animals, Cell Differentiation, Endothelium, Heart Valves, Mesoderm, Mice, Inbred C57BL, Models, Genetic, Morphogenesis, Mutation, Phenotype, In Situ Hybridization, Gene Expression Regulation, Developmental, GATA4 Transcription Factor, Mice, ErbB Receptors
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