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Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Konantz Martina, Alghisi Elisa, Müller Joëlle S, Lenard Anna, Esain Virginie, Carroll Kelli J, Kanz Lothar, North Trista E, Lengerke Claudia,
Project Role and molecular targets of the transcription factor EVI1 in lymphoblastic leukemia and blood stem cell development
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Original article (peer-reviewed)

Journal The EMBO Journal
Volume (Issue) 35(21)
Page(s) 2315 - 2331
Title of proceedings The EMBO Journal
DOI 10.15252/embj.201593454

Open Access

URL https://www.embopress.org/lookup/doi/10.15252/embj.201593454
Type of Open Access Publisher (Gold Open Access)

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.
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