Hedgehog signaling via a calcitonin receptor-like receptor can induce arterial differentiation independently of VEGF signaling in zebrafish
- Authors
- Wilkinson, R.N., Koudijs, M.J., Patient, R.K., Ingham, P.W., Schulte-Merker, S., and van Eeden, F.J.
- ID
- ZDB-PUB-120607-14
- Date
- 2012
- Source
- Blood 120(2): 477-488 (Journal)
- Registered Authors
- Ingham, Philip, Koudijs, Marco, Patient, Roger K., Schulte-Merker, Stefan, van Eeden, Freek, Wilkinson, Robert
- Keywords
- none
- MeSH Terms
-
- Hematopoietic Stem Cells/cytology
- Hematopoietic Stem Cells/metabolism
- Animals
- Arteries/embryology
- Arteries/metabolism
- Hedgehog Proteins/metabolism*
- Vascular Endothelial Growth Factor A/metabolism*
- Signal Transduction
- Animals, Genetically Modified
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Notch/metabolism
- Calcitonin Receptor-Like Protein/metabolism*
- Gene Expression Regulation, Developmental
- Gene Knockdown Techniques
- Mutation
- Zebrafish Proteins/metabolism*
- Core Binding Factor Alpha 2 Subunit/metabolism
- PubMed
- 22668851 Full text @ Blood
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.