title: Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence.
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.
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Konantz
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Alghisi
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Joëlle S
authors.initials: JS
authors.lastname: Müller
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Lenard
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Esain
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Kelli J
authors.initials: KJ
authors.lastname: Carroll
authors.affiliation: Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.|Harvard Stem Cell Institute, Cambridge, MA, USA.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland claudia.lengerke@unibas.ch.|Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.|Division of Hematology, University Hospital Basel, Basel, Switzerland.
authors.forename: Claudia
authors.identifier: 0000-0001-5442-2805
authors.initials: C
authors.lastname: Lengerke
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003959:Diamines / Q000494:pharmacology; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000612000:24-diamino-5-phenylthiazole; D004268:DNA-Binding Proteins; D003959:Diamines; D051880:Receptors, Notch; D013844:Thiazoles; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D019869:Phosphatidylinositol 3-Kinases
keywords: 
  AKT
  ; 
  VEGF
  ; EVI1; Notch; endothelial‐to‐hematopoietic transition; hematopoietic stem cells