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      Runx1 is required for the endothelial to hematopoietic cell transition but not thereafter

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          Abstract

          HSCs are the founder cells of the adult hematopoietic system, and thus knowledge of the molecular program directing their generation during development is important for regenerative hematopoietic strategies. Runx1 is a pivotal transcription factor required for HSC generation in the vascular regions of the mouse conceptus - the aorta, vitelline and umbilical arteries, yolk sac and placenta 1, 2. It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters 3 and that Runx1 functions during the transition from ‘hemogenic endothelium’ to HSCs 4, 5. Here we show by conditional deletion that Runx1 activity in vascular endothelial cadherin (VEC) positive endothelial cells is indeed essential for intra-arterial cluster, hematopoietic progenitor, and HSC formation. In contrast, Runx1 is not required in cells expressing Vav, one of the first pan-hematopoietic genes expressed in HSCs. Collectively these data show that Runx1 function is essential in endothelial cells for hematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed.

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          Most cited references27

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          A 5' element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila.

          We have characterized an element near the 5' boundary of the chicken beta-globin domain that insulates a reporter gene from the activating effects of a nearby beta-globin locus control region (5'HS2) when assayed in the human erythroid cell line K562. We show that the insulation mechanism is directional, that it operates at the level of transcription, and that it involves the alteration of chromatin structure over the promoter of the gene. The insulator has no significant stimulatory or inhibitory effects of its own. In transgenic Drosophila, the insulator protects the white minigene from position effects. The action of the insulator thus is not restricted to erythroid or mammalian cells, suggesting that such elements may serve an important and widely distributed function in the organization of chromatin structure.
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            Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo.

            The aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site within the mammalian embryo body, and the first place from which hematopoietic stem cells (HSCs) emerge. Within the complex embryonic vascular, excretory and reproductive tissues of the AGM region, the precise location of HSC development is unknown. To determine where HSCs develop, we subdissected the AGM into aorta and urogenital ridge segments and transplanted the cells into irradiated adult recipients. We demonstrate that HSCs first appear in the dorsal aorta area. Furthermore, we show that vitelline and umbilical arteries contain high frequencies of HSCs coincident with HSC appearance in the AGM. While later in development and after organ explant culture we find HSCs in the urogenital ridges, our results strongly suggest that the major arteries of the embryo are the most important sites from which definitive HSCs first emerge.
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              Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo.

              Hematopoietic stem cells (HSCs) are first found in the aorta-gonad-mesonephros region and vitelline and umbilical arteries of the midgestation mouse embryo. Runx1 (AML1), the DNA binding subunit of a core binding factor, is required for the emergence and/or subsequent function of HSCs. We show that all HSCs in the embryo express Runx1. Furthermore, HSCs in Runx1(+/-) embryos are heterogeneous and include CD45(+) cells, endothelial cells, and mesenchymal cells. Comparison with wild-type embryos showed that the distribution of HSCs among these various cell populations is sensitive to Runx1 dosage. These data provide the first morphological description of embryonic HSCs and contribute new insight into their cellular origin.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                4 May 2009
                7 January 2009
                12 February 2009
                15 September 2009
                : 457
                : 7231
                : 887-891
                Affiliations
                [1 ]Department of Biochemistry, Dartmouth Medical School, Hanover NH 03755
                [2 ]Department of Genetics, Dartmouth Medical School, Hanover NH 03755
                [3 ]Department of Cell Biology and Genetics, Erasmus University, Rotterdam, the Netherlands
                Author notes
                [5 ]Corresponding author: Nancy A. Speck, Phone: 215-898-0247, nancyas@ 123456exchange.upenn.edu
                [4]

                Current address: Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

                Article
                nihpa103020
                10.1038/nature07619
                2744041
                19129762
                b5c4556f-88e1-4b69-b416-069a5ce6eb8a
                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R37 DK054077-09 ||DK
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