title: Discrete Notch signaling requirements in the specification of hematopoietic stem cells.
abstract: Hematopoietic stem cells (HSCs) require multiple molecular inputs for proper specification, including activity of the Notch signaling pathway. A requirement for the Notch1 and dispensability of the Notch2 receptor has been demonstrated in mice, but the role of the remaining Notch receptors has not been investigated. Here, we demonstrate that three of the four Notch receptors are independently required for the specification of HSCs in the zebrafish. The orthologues of the murine Notch1 receptor, Notch1a and Notch1b, are each required intrinsically to fate HSCs, just prior to their emergence from aortic hemogenic endothelium. By contrast, the Notch3 receptor is required earlier within the developing somite to regulate HSC emergence in a non-cell-autonomous manner. Epistatic analyses demonstrate that Notch3 function lies downstream of Wnt16, which is required for HSC specification through its regulation of two Notch ligands, dlc and dld. Collectively, these findings demonstrate for the first time that multiple Notch signaling inputs are required to specify HSCs and that Notch3 performs a novel role within the somite to regulate the neighboring precursors of hemogenic endothelium.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Chase H
authors.initials: CH
authors.lastname: Melick
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Wilson K
authors.initials: WK
authors.lastname: Clements
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Stachura
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Distel
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany Cardiovascular Division, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Panáková
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA.
authors.forename: Calum
authors.initials: C
authors.lastname: MacRae
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Mork
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: J Gage
authors.initials: JG
authors.lastname: Crump
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA Section of Cell and Developmental Biology, University of California at San Diego, La Jolla, CA, USA dtraver@ucsd.edu.
authors.forename: David
authors.initials: D
authors.lastname: Traver
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D055018:Hemangioblasts / Q000166:cytology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019170:Somites / Q000166:cytology / Q000196:embryology / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C561596:Notch1b protein, zebrafish; C520425:Notch3 protein, zebrafish; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C437805:notch1a protein, zebrafish; C559646:wnt16 protein, zebrafish
keywords: Notch; hematopoietic stem cell; hemogenic endothelium; somite