title: Developing HSCs become Notch independent by the end of maturation in the AGM region.
abstract: The first definitive hematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E) 10.5 to 11 aorta-gonad-mesonephros (AGM) region. Notch signaling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signaling regulates HSC formation in the embryo is poorly understood. We demonstrate here that Notch signaling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually downregulated while they progress toward dHSCs at E11.5. This downregulation is accompanied by gradual functional loss of Notch dependency. Thus, as early as at final steps in the AGM region, HSCs begin acquiring the Notch independency characteristic of adult bone marrow HSCs as part of the maturation program. Our data indicate that fine stage-dependent tuning of Notch signaling may be required for the generation of definitive HSCs from pluripotent cells.
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Céline
authors.initials: C
authors.lastname: Souilhol
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Javier G
authors.initials: JG
authors.lastname: Lendinez
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rybtsov
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Fiona
authors.initials: F
authors.lastname: Murphy
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Heather
authors.initials: H
authors.lastname: Wilson
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Hills
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Antoniana
authors.initials: A
authors.lastname: Batsivari
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Anahí
authors.initials: A
authors.lastname: Binagui-Casas
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Alison C
authors.initials: AC
authors.lastname: McGarvey
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland;
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald
authors.affiliation: Institute for Virus Research, University of Kyoto, Kyoto, Japan; and.
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA.
authors.forename: Christian
authors.initials: C
authors.lastname: Siebel
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Suling
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine Bioquarter, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Alexander
authors.initials: A
authors.lastname: Medvinsky
mesh_terms: D000818:Animals; D001011:Aorta / Q000196:embryology* / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D006066:Gonads / Q000196:embryology* / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008650:Mesonephros / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051883:Receptor, Notch2 / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D051883:Receptor, Notch2