title: Runx1 is required for progression of CD41+ embryonic precursors into HSCs but not prior to this.
abstract: Haematopoiesis in adult animals is maintained by haematopoietic stem cells (HSCs), which self-renew and can give rise to all blood cell lineages. The AGM region is an important intra-embryonic site of HSC development and a wealth of evidence indicates that HSCs emerge from the endothelium of the embryonic dorsal aorta and extra-embryonic large arteries. This, however, is a stepwise process that occurs through sequential upregulation of CD41 and CD45 followed by emergence of fully functional definitive HSCs. Although largely dispensable at later stages, the Runx1 transcription factor is crucially important during developmental maturation of HSCs; however, exact points of crucial involvement of Runx1 in this multi-step developmental maturation process remain unclear. Here, we have investigated requirements for Runx1 using a conditional reversible knockout strategy. We report that Runx1 deficiency does not preclude formation of VE-cad+CD45-CD41+ cells, which are phenotypically equivalent to precursors of definitive HSCs (pre-HSC Type I) but blocks transition to the subsequent CD45+ stage (pre-HSC Type II). These data emphasise that developmental progression of HSCs during a very short period of time is regulated by precise stage-specific molecular mechanisms.
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Liakhovitskaia
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rybtsov
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Smith
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Antoniana
authors.initials: A
authors.lastname: Batsivari
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rybtsova
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Rode
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Marella
authors.initials: M
authors.lastname: de Bruijn
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gordon-Keylock
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Suling
authors.initials: S
authors.lastname: Zhao
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK a.medvinsky@ed.ac.uk.
authors.forename: Alexander
authors.initials: A
authors.lastname: Medvinsky
mesh_terms: D000818:Animals; D019070:Cell Lineage; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D040201:Platelet Membrane Glycoprotein IIb; C493726:Runx1 protein, mouse; C045073:Cre recombinase; D019426:Integrases
keywords: AGM region; CD41; HSC; Mouse; Runx1