PUBLICATION

Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence

Authors
Konantz, M., Alghisi, E., Müller, J.S., Lenard, A., Esain, V., Carroll, K.J., Kanz, L., North, T.E., Lengerke, C.
ID
ZDB-PUB-160918-1
Date
2016
Source
The EMBO journal   35(21): 2315-2331 (Journal)
Registered Authors
Alghisi, Elisa, Konantz, Martina, Lenard, Anna, Lengerke, Claudia, Müller, Joëlle, North, Trista
Keywords
AKT, VEGF, EVI1, Notch, endothelial‐to‐hematopoietic transition, hematopoietic stem cells
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Aorta/metabolism
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism*
  • Diamines/pharmacology
  • Embryo, Nonmammalian
  • Endothelial Cells/metabolism
  • Hematopoietic Stem Cells/metabolism*
  • Phosphatidylinositol 3-Kinases/metabolism
  • Proto-Oncogenes/genetics
  • Proto-Oncogenes/physiology*
  • Receptors, Notch/metabolism
  • Thiazoles/pharmacology
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Vascular Endothelial Growth Factor A/metabolism*
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
27638855 Full text @ EMBO J.
Abstract
During development, hematopoietic stem cells (HSCs) emerge from aortic endothelial cells (ECs) through an intermediate stage called hemogenic endothelium by a process known as endothelial-to-hematopoietic transition (EHT). While Notch signaling, including its upstream regulator Vegf, is known to regulate this process, the precise molecular control and temporal specificity of Notch activity remain unclear. Here, we identify the zebrafish transcriptional regulator evi1 as critically required for Notch-mediated EHT In vivo live imaging studies indicate that evi1 suppression impairs EC progression to hematopoietic fate and therefore HSC emergence. evi1 is expressed in ECs and induces these effects cell autonomously by activating Notch via pAKT Global or endothelial-specific induction of notch, vegf, or pAKT can restore endothelial Notch and HSC formations in evi1 morphants. Significantly, evi1 overexpression induces Notch independently of Vegf and rescues HSC numbers in embryos treated with a Vegf inhibitor. In sum, our results unravel evi1-pAKT as a novel molecular pathway that, in conjunction with the shh-vegf axis, is essential for activation of Notch signaling in VDA endothelial cells and their subsequent conversion to HSCs.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes