NFAT directly regulates Nkx2-5 transcription during cardiac cell differentiation.

Abstract:

BACKGROUND INFORMATION:The transcription factor NFAT (nuclear factor of activated T-cell) family comprises important regulators in immuno-responses and mouse embryonic development, including early cardiovascular and heart valve development. The mechanism involved, however, is not fully understood. Nkx2-5 (NK2 transcription factor related, locus 5) is one of the earliest genes expressed in early cardiac progenitor cells and is essential for heart tube development by control of a subset of cardiac muscle-specific genes. Previously we found that downregulation of mitochondrial respiratory chain complex I caused severe cardiac deficiencies during heart tube development in Xenopus embryos associated with compromised Nkx2-5 expression. However, the heart defects and Nkx2-5 expression could be rescued by a constitutively activated NFAT, suggesting a possible link between NFAT and Nkx2-5 during early heart development. RESULTS:In the present study, we demonstrate that NFAT regulates Nkx2-5 expression in both mouse ES (embryonic stem) cells and P19 cells, a mouse model for embryonic differentiation. We found that there are six core NFAT-binding elements in the 5' regulatory region of the Nkx2-5 gene. Although NFAT is able to bind directly to all but one of these elements, it activates Nkx2-5 transcription only via a specific binding site in the distal enhancer region. Interestingly, the transcriptional activity of NFAT is largely dependent on the co-factor GATA (GATA-binding transcription factor), which binds to an element adjacent to this key NFAT-binding site. Furthermore, binding of the endogenous NFAT to this particular site was observed during cardiac differentiation in mouse ES and P19 cells. CONCLUSIONS:The results suggest that Nkx2-5 is a direct target of NFAT that co-ordinates with other transcription factors such as GATA4 to regulate Nkx2-5 during cardiogenesis.

journal_name

Biol Cell

journal_title

Biology of the cell

authors

Chen Y,Cao X

doi

10.1042/BC20080108

subject

Has Abstract

pub_date

2009-06-01 00:00:00

pages

335-49

issue

6

eissn

0248-4900

issn

1768-322X

pii

BC20080108

journal_volume

101

pub_type

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