Wilkinson, R.N., Koudijs, M.J., Patient, R.K., Ingham, P.W., Schulte-Merker, S., and van Eeden, F.J. (2012) Hedgehog signaling via a calcitonin receptor-like receptor can induce arterial differentiation independently of VEGF signaling in zebrafish. Blood. 120(2):477-488.
Multiple signalling pathways control the specification of endothelial cells (ECs) to become arteries or veins during vertebrate
embryogenesis. Current models propose that a cascade of Hedgehog (Hh), Vascular Endothelial Growth Factor (VEGF) and Notch
signalling acts instructively on ECs to control the choice between arterial or venous fate. Differences in the phenotypes
induced by Hh, VEGF or Notch inhibition suggest that not all of the effects of Hh on arterial-venous specification, are mediated
by VEGF. We establish that full derepression of the Hh pathway in ptc1;ptc2 mutants converts the posterior cardinal vein into a second arterial vessel that manifests intact arterial gene expression,
intersegmental vessel sprouting and haematopoietic stem cell (HSC) gene expression. Importantly, whilst VEGF was thought to
be absolutely essential for arterial fates, we find that normal and ectopic arterial differentiation can occur without VEGF
signalling in ptc1;ptc2 mutants. Furthermore, Hh is able to bypass VEGF to induce arterial differentiation in ECs via the calcitonin receptor-like
receptor, thus revealing a surprising complexity in the interplay between Hh and VEGF signalling during arteriovenous specification.
Finally, our experiments establish a dual function of Hedgehog during induction of runx1+ HSCs.