Nfatc1 Coordinates Valve Endocardial Cell Lineage Development Required for Heart Valve Formation
Open accessAbstract
Rationale: Formation of heart valves requires early endocardial to mesenchymal transformation (EMT) to generate valve mesenchyme and subsequent endocardial cell proliferation to elongate valve leaflets. Nfatc1 (nuclear factor of activated T cells, cytoplasmic 1) is highly expressed in valve endocardial cells and is required for normal valve formation, but its role in the fate of valve endocardial cells during valve development is unknown. Objective: Our aim was to investigate the function of Nfatc1 in cell-fate decision making by valve endocardial cells during EMT and early valve elongation. Methods and Results: Nfatc1 transcription enhancer was used to generate a novel valve endocardial cell–specific Cre mouse line for fate-mapping analyses of valve endocardial cells. The results demonstrate that a subpopulation of valve endocardial cells marked by the Nfatc1 enhancer do not undergo EMT. Instead, these cells remain within the endocardium as a proliferative population to support valve leaflet extension. In contrast, loss of Nfatc1 function leads to enhanced EMT and decreased proliferation of valve endocardium and mesenchyme. The results of blastocyst complementation assays show that Nfatc1 inhibits EMT in a cell-autonomous manner. We further reveal by gene expression studies that Nfatc1 suppresses transcription of Snail1 and Snail2, the key transcriptional factors for initiation of EMT. Conclusions: These results show that Nfatc1 regulates the cell-fate decision making of valve endocardial cells during valve development and coordinates EMT and valve elongation by allocating endocardial cells to the 2 morphological events essential for valve development.
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VEGF signalling induces NFATc1 expression, which represses EndMT and maintains endothelial identity in non-transitioning endocardium.
“VEGF signalling is also implicated – inducing NFATc1 expression, which represses EndMT and maintains endothelial identity in non-transitioning endocardium21.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [21]
The Results section on EMT and cell-cell contact says Nfatc1 maintains the endocardial phenotype by suppressing Snail2. The Discussion and fate-mapping results also support its role in limiting EMT in valve endocardial cells that remain in the endocardium. Our copy does not establish the attributed upstream step that VEGF signalling induces Nfatc1 expression. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAt E10.5, NFATc1 co-expression is observed on the flow-side of the cushions with ERG and within the VECs lining the primitive valves at E11.5.
“At E10.5, we observe NFATc1 co-expression on the flow-side of the cushions with ERG and within the VECs lining the primitive valves at E11.521,48”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [21]
The Results section reports Nfatc1-high cells in the cushion endocardium at E10.5 and continued expression in valve endocardial cells from E11.5; the Discussion likewise describes high Nfatc1 expression during valve elongation. Our copy does not establish co-expression with ERG or locate those cells specifically on the flow-side of the cushions. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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- Authors
- Wu, B., Wang, Y., Lui, W., Langworthy, M., Tompkins, K. L., Hatzopoulos, A. K., Baldwin, H. S., & Zhou, B.
- Affiliations
- Albert Einstein College of Medicine (US)
- Venue
- Circulation Research
- Published
- 2011-07-08
- Volume
- 109
- Issue
- 2
- Pages
- 183-192
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3132827
- OpenAlex
- W2157780291
- Cited by
- 182
- References
- 53
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 13 · 2023: 12 · 2022: 14 · 2021: 15 · 2020: 14 · 2019: 12 · 2018: 16 · 2017: 6 · 2016: 15 · 2015: 14 · 2014: 16 · 2013: 10 · 2012: 12
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1f32hl007881-01)
- National Heart, Lung, and Blood Institute (HL104441, R01HL078881, HL07881, HL07881S, U01HL100398, RL1 HL0952551, R21HL104444)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- NFATc1, heart valve development, cell fate determination, SNAI1, Snail2, transcriptional repression, fate mapping, cell proliferation
- MeSH terms
- Snail Family Transcription Factors, Animals, Endocardium, Heart Valves, Morphogenesis, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Developmental, Cell Lineage, Organogenesis, NFATC Transcription Factors, Mice, Epithelial-Mesenchymal Transition
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