Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa

Akiyama, Haruhiko; Chaboissier, Marie-Christine; Behringer, Richard R.; Rowitch, David H.; Schedl, Andreas; Epstein, Jonathan A.; de Crombrugghe, Benoit

doi:10.1073/pnas.0401711101

Cited by 265Congenital heart defects researchDevelopmental Biology and Gene RegulationCardiac electrophysiology and arrhythmias

Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa

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Akiyama, Haruhiko, Chaboissier, Marie-Christine, Behringer, Richard R., Rowitch, David H., Schedl, Andreas, Epstein, Jonathan A., de Crombrugghe, Benoit·2004·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0401711101PMC PMC404074

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Abstract

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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Sox9fl/fl;Tie2-cre embryos die around E12.5 with AV developmental defects characterized by severe cushion hypoplasia.
“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]
The Results report severely underdeveloped AV endocardial cushions in Sox9-null embryos, but say those embryos died between 11.5 and 12.0 dpc, rather than around E12.5. The Materials and Methods describe Zp3-Cre, Prm1-Cre, and Wnt1-Cre crosses, not Sox9fl/fl;Tie2-Cre embryos. The cited paper therefore supports the cushion defect in a different mutant, not the full genotype-specific claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured
SOX9 is crucial for EMT and EndMT.
“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]
The paper states that Sox9 has an essential role in EMT in the heart, specifically in endocardial endothelial cells forming cardiac cushions (opening section; Discussion). This supports its importance in cardiac EndMT, but the paper only suggests analogous roles in other organs; it does not establish that SOX9 is crucial for EMT more generally. (LLM, conf=0.82)
Experimental — accuracy not yet measured
In mouse, SOX9 is essential for the EndMT process that produces functioning heart valves.
“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]
The paper’s introductory passage states that Sox9 has an essential role in cardiac EMT, and describes endocardial cushions as the primordia of valves and septa. The Results report hypoplastic cushions in Sox9-null mouse embryos. The copy does not establish that this process produces functioning valves or assess valve function. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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 [17]
SOX9 is critical for AV valve development, including EndMT and matrix remodelling.
“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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The transcription factor Znf219 regulates chondrocyte differentiation by assembling a transcription factory with Sox9
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Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells
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Sox9b Is Required for Epicardium Formation and Plays a Role in TCDD-Induced Heart Malformation in Zebrafish
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Arid5a cooperates with Sox9 to stimulate chondrocyte-specific transcription
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Hydroureternephrosis due to loss of Sox9-regulated smooth muscle cell differentiation of the ureteric mesenchyme
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SOX9 modulates the expression of key transcription factors required for heart valve development
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Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development
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Analysis of transcriptional targets of SOX9 during embryonic heart valve development reveals a critical network of transcription factors
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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: Akiyama, Haruhiko
Chaboissier, Marie-Christine
Behringer, Richard R.
Rowitch, David H.
Schedl, Andreas
Epstein, Jonathan A.
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
DOI: 10.1073/pnas.0401711101
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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Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa

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