TY - JOUR
T1 - Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract
AU - Seo, Seungwoon
AU - Kume, Tsutomu
N1 - Funding Information:
We thank Drs. David Bader, Joey Barnett, Scott Baldwin, Christopher Brown, and Bin Zhou for helpful discussions. This work was supported by grants from the NIH (HL67105 and HL74121) and the March of Dimes Birth Defects Foundation to T.K.
PY - 2006/8/15
Y1 - 2006/8/15
N2 - Previous studies have shown that Foxc1 and Foxc2, closely related Fox transcription factors, have interactive roles in cardiovascular development. However, little is known about their functional overlap during early heart morphogenesis. Here, we show that Foxc genes are coexpressed in a novel heart field, the second heart field, as well as the cardiac neural crest cells (NCCs), endocardium, and proepicardium. Notably, compound Foxc1; Foxc2 mutants have a wide spectrum of cardiac abnormalities, including hypoplasia or lack of the outflow tract (OFT) and right ventricle as well as the inflow tract, dysplasia of the OFT and atrioventricular cushions, and abnormal formation of the epicardium, in a dose-dependent manner. Most importantly, in the second heart field, compound mutants exhibit significant downregulation of Tbx1 and Fgf8/10 and a reduction in cell proliferation. Moreover, NCCs in compound mutants show extensive apoptosis during migration, leading to a failure of the OFT septation. Taken together, our results demonstrate that Foxc1 and Foxc2 play pivotal roles in the early processes of heart development, especially acting upstream of the Tbx1-FGF cascade during the morphogenesis of the OFT.
AB - Previous studies have shown that Foxc1 and Foxc2, closely related Fox transcription factors, have interactive roles in cardiovascular development. However, little is known about their functional overlap during early heart morphogenesis. Here, we show that Foxc genes are coexpressed in a novel heart field, the second heart field, as well as the cardiac neural crest cells (NCCs), endocardium, and proepicardium. Notably, compound Foxc1; Foxc2 mutants have a wide spectrum of cardiac abnormalities, including hypoplasia or lack of the outflow tract (OFT) and right ventricle as well as the inflow tract, dysplasia of the OFT and atrioventricular cushions, and abnormal formation of the epicardium, in a dose-dependent manner. Most importantly, in the second heart field, compound mutants exhibit significant downregulation of Tbx1 and Fgf8/10 and a reduction in cell proliferation. Moreover, NCCs in compound mutants show extensive apoptosis during migration, leading to a failure of the OFT septation. Taken together, our results demonstrate that Foxc1 and Foxc2 play pivotal roles in the early processes of heart development, especially acting upstream of the Tbx1-FGF cascade during the morphogenesis of the OFT.
KW - Cushion mesenchyme
KW - Epicardium
KW - Forkhead
KW - Heart development
KW - Neural crest
KW - Outflow tract
KW - Second heart field
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U2 - 10.1016/j.ydbio.2006.06.012
DO - 10.1016/j.ydbio.2006.06.012
M3 - Article
C2 - 16839542
AN - SCOPUS:33746926015
SN - 0012-1606
VL - 296
SP - 421
EP - 436
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -