The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
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 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]
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“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]
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Citations
Cites
Tie2-Cre Transgenic Mice: A New Model for Endothelial Cell-Lineage Analysis in Vivo
Kisanuki, Y. Y., Hammer, R. E., Miyazaki, J.-I., Williams, S. C., Richardson, J. A., & Yanagisawa, M. (2001) · Developmental Biology · doi:10.1006/dbio.2000.0106 · Cited by 1,241
Fate of the mammalian cardiac neural crest
Jiang, X., Rowitch, D. H., Soriano, P. M., McMahon, A. P., & Sucov, H. M. (2000) · Development · doi:10.1242/dev.127.8.1607 · Cited by 1,172
Autoamplification of NFATc1 expression determines its essential role in bone homeostasis
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Clinical and Pathophysiological Implications of a Bicuspid Aortic Valve
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Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum
de la Pompa, J. L., Timmerman, L. A., Takimoto, H., Yoshida, H., Elia, A. J., Samper, E., Potter, J., Wakeham, A., Marengere, L., Langille, B. L., et al. (1998) · Nature · doi:10.1038/32419 · Cited by 660
Molecular Regulation of Atrioventricular Valvuloseptal Morphogenesis
Eisenberg, L. M., & Markwald, R. R. (1995) · Circulation Research · doi:10.1161/01.res.77.1.1 · Cited by 654
The transcription factor NF-ATc is essential for cardiac valve formation
Ranger, A. M., Grusby, M. J., Hodge, M. R., Gravallese, E. M., de la Brousse, F. C., Hoey, T., Mickanin, C., Baldwin, H. S., & Glimcher, L. H. (1998) · Nature · doi:10.1038/32426 · Cited by 586
Self-citationA role for Smad6 in development and homeostasis of the cardiovascular system
Galvin, K. M., Donovan, M. J., Lynch, C. A., Meyer, R. I., Paul, R. J., Lorenz, J. N., Fairchild-Huntress, V., Dixon, K. L., Dunmore, J. H., Gimbrone, M. A., et al. (2000) · Nature Genetics · doi:10.1038/72835 · Cited by 507
Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4
Schilham, M. W., Oosterwegel, M. A., Moerer, P., Ya, J., de Boer, P. A. J., van de Wetering, M., Verbeek, S. J., Lamers, W. H., Kruisbeek, A. M., Cumano, A., et al. (1996) · Nature · doi:10.1038/380711a0 · Cited by 480
Cited by
Sorted by citations
Epithelial-to-Mesenchymal and Endothelial-to-Mesenchymal Transition
Kovacic, J. C., Mercader, N., Torres, M., Boehm, M., & Fuster, V. (2012) · Circulation · doi:10.1161/circulationaha.111.040352 · Cited by 420
Wu, B., Zhang, Z., Lui, W., Chen, X., Wang, Y., Chamberlain, A. A., Moreno‐Rodriguez, R. A., Markwald, R. R., O'Rourke, B. P., Sharp, D. J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.023 · Cited by 402
Self-citationMitral valve disease—morphology and mechanisms
Levine, R. A., Hagège, A. A., Judge, D. P., Padala, M., Dal‐Bianco, J. P., Aikawa, E. R., Beaudoin, J., Bischoff, J. E., Bouatia‐Naji, N., Bruneval, P., et al. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.161 · Cited by 389
Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases
Li, Y., Lui, K. O., & Zhou, B. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0023-y · Cited by 287
Self-citationThe deployment of cell lineages that form the mammalian heart
Meilhac, S. M., & BUCKINGHAM, M. E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0086-9 · Cited by 262
Metadata
- 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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