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Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa
Open accessAbstract
Epithelial–mesenchymal transformation is a critical developmental process reiterated in multiple organs throughout embryogenesis. Formation of endocardial cushions, primordia of valves and septa, is a classic example of epithelial–mesenchymal transformation. Several gene mutations are known to affect cardiac valve formation. Sox9 is activated when endocardial endothelial cells undergo mesenchymal transformation and migrate into an extracellular matrix, called cardiac jelly, to form endocardial cushions. In Sox9 -null mutants, endocardial cushions are markedly hypoplastic. In these mutants, Nfatc1 is ectopically expressed and no longer restricted to endothelial cells. Further, Sox9-deficient endocardial mesenchymal cells fail to express ErbB3 , which is required for endocardial cushion cell differentiation and proliferation. Our results reveal a succession of molecular steps in the pathway of endocardial cushion development. We propose that loss of Sox9 inhibits epithelial–mesenchymal transformation after delamination and initial migration, but before definitive mesenchymal transformation.
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“These embryos die around E12.5 with AV developmental defects, characterized by severe cushion hypoplasia17.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [17]
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“SOX9 is also crucial for processes involving epithelial-to-mesenchymal transition (EMT) and the closely related process endothelial-to-mesenchymal transition (EndMT) (10–12).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [11]
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“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [11]
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“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 [17]
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“SOX9 is critical for AV valve development, including in EndMT and matrix remodelling16,17,51,52”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [17]
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“During cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and where SOX9 activates transcription of key regulators of heart valve development (11,17).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [11]
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“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [11]
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Metadata
- Authors
- Akiyama, H., Chaboissier, M.-C., Behringer, R. R., Rowitch, D. H., Schedl, A., Epstein, J. A., & de Crombrugghe, B.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; Institut National de la Santé et de la Recherche Médicale U470, Centre de Biochimie, Parc Valrose, 06108 Nice Cedex 2, France; Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; and Cardiovascular Division, University of Pennsylvania, Philadelphia, PA 19104
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-04-19
- Volume
- 101
- Issue
- 17
- Pages
- 6502-6507
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC404074
- OpenAlex
- W2029022250
- Cited by
- 265
- References
- 41
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 3 · 2023: 11 · 2022: 19 · 2021: 11 · 2020: 11 · 2019: 10 · 2018: 13 · 2017: 13 · 2016: 2 · 2015: 14 · 2014: 9 · 2013: 17 · 2012: 14
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA-16 672)
- National Cancer Institute (CA-16672, P30CA016672)
- 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
- SOX9, endocardial cushion, epithelial-mesenchymal transition, NFATc1, HER3, cardiac jelly, endocardial endothelial cells, heart development
- MeSH terms
- Animals, Cell Division, Female, Heart Septum, Heart Valves, High Mobility Group Proteins, Mesoderm, Mice, Transgenic, Mutation, Pregnancy, Transcription Factors, Receptor, ErbB-3, Mice, SOX9 Transcription Factor
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