title: Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium.
abstract: Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage-tracing studies have established that definitive hematopoietic stem and progenitor cells arise from vascular endothelial-cadherin(+) hemogenic endothelial cells of the aorta-gonad-mesonephros region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and we identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis.
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA; Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea;
authors.forename: Il Ho
authors.initials: IH
authors.lastname: Jang
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA;
authors.forename: Long
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Wenzel
authors.affiliation: Northwestern University, Chicago, IL;
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA;
authors.forename: Sumon M
authors.initials: SM
authors.lastname: Datta
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: Natasha
authors.initials: N
authors.lastname: Arora
authors.affiliation: Cancer Research Program, Institut Hospital del Mar Investigacions Mediques, Barcelona, Spain; and.
authors.forename: Jordi
authors.initials: J
authors.lastname: Guiu
authors.affiliation: Centre National de la Recherche Scientifique Unité de Recherche Associée 2578, Department of Developmental Biology, Pasteur Institute, Paris, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Lagha
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea;
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Do
authors.affiliation: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea;
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Schlaeger
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: Cancer Research Program, Institut Hospital del Mar Investigacions Mediques, Barcelona, Spain; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.affiliation: Harvard Stem Cell Institute, Boston, MA; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA;
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Burns
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA;
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; C082078:mesenchyme fork head 1 protein