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First published online September 1, 2004
doi: 10.1242/10.1242/dev.01310
1 Howard Hughes Medical Institute and Abramson Family Cancer Research Institute,
University of Pennsylvania School of Medicine, Philadelphia, PA 19104,
USA
2 Abramson Family Cancer Research Institute, University of Pennsylvania School
of Medicine, Philadelphia, PA 19104, USA
3 Department of Immunology, Medical Faculty/University Clinics, 89070 Ulm,
Germany
4 Carl C, Icahn Center for Gene Therapy and Molecular Medicine, Mount Sinai
School of Medicine, New York, NY 10029, USA
* Author for correspondence (e-mail: celeste2{at}mail.med.upenn.edu)
Accepted 15 June 2004
Hypoxia Inducible Factor (HIF), consisting of HIF1
and ARNT
(HIF1ß) subunits, activates multiple genes in response to oxygen
(O2) deprivation. Arnt–/– mice
exhibit substantial defects in blood cell and vessel development. We
demonstrate that hypoxia accelerates the expression of Brachyury (a
mesoderm-specific transcription factor), BMP4 (a mesoderm-promoting growth
factor) and FLK1 (a marker of hemangioblasts, the bipotential progenitor of
endothelial and hematopoietic cells) in differentiating ES cell cultures.
Significantly, proliferation of embryonic hemangioblasts (BL-CFCs) is
regulated by hypoxia, as Arnt+/+ ES cells generate
increased numbers of FLK1+ cells, and BL-CFCs with accelerated
kinetics in response to low O2. This response is HIF-dependent as
Arnt–/– ES cells produce fewer
FLK1+ cells and BL-CFCs, under both normoxic and hypoxic
conditions. Interestingly, this defect is rescued when
Arnt–/– ES cells are co-cultured with
Arnt+/+ ES cells. Vegf+/–or
Vegf–/– ES cells generate proper numbers of
FLK1+ cells but fewer BL-CFCs, suggesting that additional factors
regulated by HIF (other than VEGF) are involved in these early events. Thus,
hypoxic responses are important for the establishment of various progenitor
cells, including early mesoderm and its differentiation into hemangioblasts.
Together these data suggest that ineffective responses to hypoxia in
Arnt–/– embryos abrogate proper cardiovascular
development during early embryogenesis, including the pathways controlling
hemangioblast differentiation.
Key words: HIF, ARNT, Hypoxia, Hemangioblast, Mesoderm
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