TY - JOUR
T1 - The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development
AU - Seo, Seungwoon
AU - Fujita, Hideo
AU - Nakano, Atsushi
AU - Kang, Myengmo
AU - Duarte, Antonio
AU - Kume, Tsutomu
N1 - Funding Information:
We thank Drs. Jose Goumans and Peter ten Dijke for generously providing MEECs. We also thank Drs. Brigid Hogan, Yohsuke Mukouyama, Lucy Liaw, David Bader, and Joey Barnett for the helpful comments and discussions on the manuscript. This work was supported by funding from the NIH to T. K. (HL67105 and HL74121).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2006/6/15
Y1 - 2006/6/15
N2 - Accumulating evidence suggests that in the vertebrate embryo, acquisition of arterial and venous identity is established early by genetic mechanisms, including those regulated by vascular endothelial growth factor (VEGF) and Notch signaling. However, although the COUP-TFII nuclear receptor has recently been shown to regulate vein identity, very little is known about the molecular mechanisms of transcriptional regulation in arterial specification. Here, we show that mouse embryos compound mutant for Foxc1 and Foxc2, two closely related Fox transcription factors, exhibit arteriovenous malformations and lack of induction of arterial markers whereas venous markers such as COUP-TFII are normally expressed, suggesting that mutant endothelial cells fail to acquire an arterial fate. Notably, consistent with this observation, overexpression of Foxc genes in vitro induces expression of arterial markers such as Notch1 and its ligand Delta-like 4 (Dll4), and Foxc1 and Foxc2 directly activate the Dll4 promoter via a Foxc-binding site. Moreover, compound Foxc mutants show a defect in sprouting of lymphatic endothelial cells from veins in early lymphatic development, due to reduced expression of VEGF-C. Taken together, our results demonstrate that Foxc transcription factors are novel regulators of arterial cell specification upstream of Notch signaling and lymphatic sprouting during embryonic development.
AB - Accumulating evidence suggests that in the vertebrate embryo, acquisition of arterial and venous identity is established early by genetic mechanisms, including those regulated by vascular endothelial growth factor (VEGF) and Notch signaling. However, although the COUP-TFII nuclear receptor has recently been shown to regulate vein identity, very little is known about the molecular mechanisms of transcriptional regulation in arterial specification. Here, we show that mouse embryos compound mutant for Foxc1 and Foxc2, two closely related Fox transcription factors, exhibit arteriovenous malformations and lack of induction of arterial markers whereas venous markers such as COUP-TFII are normally expressed, suggesting that mutant endothelial cells fail to acquire an arterial fate. Notably, consistent with this observation, overexpression of Foxc genes in vitro induces expression of arterial markers such as Notch1 and its ligand Delta-like 4 (Dll4), and Foxc1 and Foxc2 directly activate the Dll4 promoter via a Foxc-binding site. Moreover, compound Foxc mutants show a defect in sprouting of lymphatic endothelial cells from veins in early lymphatic development, due to reduced expression of VEGF-C. Taken together, our results demonstrate that Foxc transcription factors are novel regulators of arterial cell specification upstream of Notch signaling and lymphatic sprouting during embryonic development.
KW - Arterial-venous specification
KW - Forkhead
KW - Lymphatic development
KW - Notch
KW - VEGF
KW - Vascular development
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U2 - 10.1016/j.ydbio.2006.03.035
DO - 10.1016/j.ydbio.2006.03.035
M3 - Article
C2 - 16678147
AN - SCOPUS:33745099879
VL - 294
SP - 458
EP - 470
JO - Developmental Biology
JF - Developmental Biology
SN - 0012-1606
IS - 2
ER -