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

Bingruo Wu, Yidong Wang, Wendy Lui, Melissa Langworthy, Kevin L. Tompkins, Antonis K. Hatzopoulos, H. Scott Baldwin, Bin Zhou

Research output: Contribution to journalArticle

83 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)183-192
Number of pages10
JournalCirculation Research
Volume109
Issue number2
DOIs
StatePublished - Jul 8 2011

Fingerprint

NFATC Transcription Factors
Heart Valves
Cell Lineage
Endocardium
Mesoderm
Decision Making
Peptide Initiation Factors
Blastocyst

Keywords

  • congenital
  • endocardium
  • heart defects
  • valves

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation. / Wu, Bingruo; Wang, Yidong; Lui, Wendy; Langworthy, Melissa; Tompkins, Kevin L.; Hatzopoulos, Antonis K.; Baldwin, H. Scott; Zhou, Bin.

In: Circulation Research, Vol. 109, No. 2, 08.07.2011, p. 183-192.

Research output: Contribution to journalArticle

Wu, B, Wang, Y, Lui, W, Langworthy, M, Tompkins, KL, Hatzopoulos, AK, Baldwin, HS & Zhou, B 2011, 'Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation', Circulation Research, vol. 109, no. 2, pp. 183-192. https://doi.org/10.1161/CIRCRESAHA.111.245035
Wu, Bingruo ; Wang, Yidong ; Lui, Wendy ; Langworthy, Melissa ; Tompkins, Kevin L. ; Hatzopoulos, Antonis K. ; Baldwin, H. Scott ; Zhou, Bin. / Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation. In: Circulation Research. 2011 ; Vol. 109, No. 2. pp. 183-192.
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AB - 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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