Hedgehog signaling induces arterial endothelial cell formation by repressing venous cell fate.
In vertebrate embryos, the dorsal aorta and the posterior cardinal vein form in the trunk to comprise the original circulatory loop. Previous studies implicate Hedgehog (Hh) signaling in the development of the dorsal aorta. However, the mechanism controlling specification of artery versus vein remains unclear. Here, we investigated the cell-autonomous mechanism of Hh signaling in angioblasts (endothelial progenitor cells) during arterial-venous specification utilizing zebrafish mutations in Smoothened (Smo), a G protein-coupled receptor essential for Hh signaling. smo mutants exhibit an absence of the dorsal aorta accompanied by a reciprocal expansion of the posterior cardinal vein. The increased number of venous cells is equivalent to the loss of arterial cells in embryos with loss of Smo function. Activation of Hh signaling expands the arterial cell population at the expense of venous cell fate. Time-lapse imaging reveals two sequential waves of migrating progenitor cells that contribute to the dorsal aorta and the posterior cardinal vein, respectively. Angioblasts deficient in Hh signaling fail to contribute to the arterial wave; instead, they all migrate medially as a single population to form the venous wave. Cell transplantation analyses demonstrate that Smo plays a cell-autonomous role in specifying angioblasts to become arterial cells, and Hh signaling-depleted angioblasts differentiate into venous cells instead. Collectively, these studies suggest that arterial endothelial cells are specified and formed via repressing venous cell fate at the lateral plate mesoderm by Hh signaling during vasculogenesis.
Williams
Charles
C
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
Kim
Seok-Hyung
SH
Ni
Terri T
TT
Mitchell
Lauren
L
Ro
Hyunju
H
Penn
John S
JS
Baldwin
Scott H
SH
Solnica-Krezel
Lila
L
Zhong
Tao P
TP
D000818:Animals; D001158:Arteries / Q000196:embryology*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014680:Veins / Q000196:embryology*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism
D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D029961:Zebrafish Proteins; C491021:smo protein, zebrafish