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Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence
Author(s) -
Konantz Martina,
Alghisi Elisa,
Müller Joëlle S,
Lenard Anna,
Esain Virginie,
Carroll Kelli J,
Kanz Lothar,
North Trista E,
Lengerke Claudia
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593454
Subject(s) - biomedicine , medicine , biology , bioinformatics
During development, hematopoietic stem cells ( HSC s) emerge from aortic endothelial cells ( EC s) 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 EC s 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.