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    Regulation of RUNX1 dosage is crucial for efficient blood formation from hemogenic endothelium.

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    Authors
    Lie-A-Ling, Michael
    Marinopoulou, Elli
    Lilly, Andrew J
    Challinor, Mairi
    Patel, Rahima
    Lancrin, C
    Kouskoff, Valerie
    Lacaud, Georges
    Affiliation
    Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
    Issue Date
    2018
    
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    Abstract
    During ontogeny, hematopoietic stem and progenitor cells arise from hemogenic endothelium through an endothelial-to-hematopoietic transition that is strictly dependent on the transcription factor RUNX1. Although it is well established that RUNX1 is essential for the onset of hematopoiesis, little is known about the role of RUNX1 dosage specifically in hemogenic endothelium and during the endothelial-to-hematopoietic transition. Here, we used the mouse embryonic stem cell differentiation system to determine if and how RUNX1 dosage affects hemogenic endothelium differentiation. The use of inducibleRunx1expression combined with alterations in the expression of the RUNX1 co-factor CBFβ allowed us to evaluate a wide range of RUNX1 levels. We demonstrate that low RUNX1 levels are sufficient and necessary to initiate an effective endothelial-to-hematopoietic transition. Subsequently, RUNX1 is also required to complete the endothelial-to-hematopoietic transition and to generate functional hematopoietic precursors. In contrast, elevated levels of RUNX1 are able to drive an accelerated endothelial-to-hematopoietic transition, but the resulting cells are unable to generate mature hematopoietic cells. Together, our results suggest that RUNX1 dosage plays a pivotal role in hemogenic endothelium maturation and the establishment of the hematopoietic system.
    Citation
    Regulation of RUNX1 dosage is crucial for efficient blood formation from hemogenic endothelium. 2018, 145(5): Development
    Journal
    Development
    URI
    http://hdl.handle.net/10541/620885
    DOI
    10.1242/dev.149419
    PubMed ID
    29530939
    Type
    Article
    Language
    en
    ISSN
    1477-9129
    ae974a485f413a2113503eed53cd6c53
    10.1242/dev.149419
    Scopus Count
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    All Paterson Institute for Cancer Research

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