title: Interferon gamma signaling positively regulates hematopoietic stem cell emergence.
abstract: Vertebrate hematopoietic stem cells (HSCs) emerge in the aorta-gonad-mesonephros (AGM) region from "hemogenic" endothelium. Here we show that the proinflammatory cytokine interferon-γ (IFN-γ) and its receptor Crfb17 positively regulate HSC development in zebrafish. This regulation does not appear to modulate the proliferation or survival of HSCs or endothelial cells, but rather the endothelial-to-HSC transition. Notch signaling and blood flow positively regulate the expression of ifng and crfb17 in the AGM. Notably, IFN-γ overexpression partially rescues the HSC loss observed in the absence of blood flow or Notch signaling. Importantly, IFN-γ signaling acts cell autonomously to control the endothelial-to-HSC transition. IFN-γ activates Stat3, an atypical transducer of IFN-γ signaling, in the AGM, and Stat3 inhibition decreases HSC formation. Together, our findings uncover a developmental role for an inflammatory cytokine and place its action downstream of Notch signaling and blood flow to control Stat3 activation and HSC emergence.
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany. Electronic address: suphansa.sawamiphak@mpi-bn.mpg.de.
authors.forename: Suphansa
authors.initials: S
authors.lastname: Sawamiphak
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Kontarakis
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany. Electronic address: didier.stainier@mpi-bn.mpg.de.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D019070:Cell Lineage; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D008650:Mesonephros / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*
chemical_list: D007371:Interferon-gamma