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EMBO J. 2016 Nov 2;35(21):2315-2331. Epub 2016 Sep 16.

Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence.

Author information

1
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
2
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
3
Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.
4
Harvard Stem Cell Institute, Cambridge, MA, USA.
5
Department of Biomedicine, University Hospital Basel, Basel, Switzerland claudia.lengerke@unibas.ch.
6
Division of Hematology, University Hospital Basel, Basel, Switzerland.

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.

KEYWORDS:

AKT ; VEGF ; EVI1; Notch; endothelial‐to‐hematopoietic transition; hematopoietic stem cells

PMID:
27638855
PMCID:
PMC5090218
DOI:
10.15252/embj.201593454
[Indexed for MEDLINE]
Free PMC Article

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