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Circ Res. 2011 Jul 8;109(2):183-92. doi: 10.1161/CIRCRESAHA.111.245035. Epub 2011 May 19.

Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation.

Author information

1
Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Price Center 420, 1301 Morris Park Ave, Bronx, NY 10461, USA.

Abstract

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.

PMID:
21597012
PMCID:
PMC3132827
DOI:
10.1161/CIRCRESAHA.111.245035
[Indexed for MEDLINE]
Free PMC Article
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