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Oxygen tension modulates ß-globin switching in embryoid bodies

^a Institute of Physiology, University of Zürich-Irchel, 8057 Zürich, Switzerland;

^b Max-Planck-Institute for Molecular Physiology, 44026 Dortmund, Germany; and

^c Institute of Physiology, Medical University of Lübeck, 23538 Lübeck, Germany

Little is known about the factors influencing the hemoglobin switch in vertebrates during development. Inasmuch as the mammalian conceptus is exposed to changing oxygen tensions in utero, we examined the effect of different oxygen concentrations on ß-globin switching. We used an in vitro model of mouse embryogenesis based on the differentiation of blastocyst-derived embryonic stem cells to embryoid bodies (EBs). Cultivation of EBs at increasing oxygen concentrations (starting at 1% O₂) did not influence the temporal expression pattern of embryonic (ßH1) globin compared to the normoxic controls (20% O₂). In contrast, when compared to normoxically grown EBs, expression of fetal/adult (ß^maj) globin in EBs cultured at varying oxygen concentrations was delayed by about 2 days and persisted throughout differentiation. Quantitation of hemoglobin in EBs using a 2,7-diaminofluorene-based colorimetric assay revealed the appearence of hemoglobin in two waves, an early and a late one. This observation was verified by spectrophotometric analysis of hemoglobin within single EBs. These two waves might reflect the switch of erythropoiesis from yolk sac to fetal liver. Reduced oxygenation is known to activate the hypoxia-inducible factor-1 (HIF-1), which in turn specifically induces expression of a variety of genes among them erythropoietin (EPO). Although EBs increased EPO expression upon hypoxic exposure, the altered ß-globin appearance was not related to EPO levels as determined in EBs overexpressing EPO. Since mRNA from both mouse HIF-1 isoforms was detected in all EBs tested at different differentiation stages, we propose that HIF-1 modulates ß-globin expression during development.—Bichet, S., Wenger, R. H., Camenisch, G., Rolfs, A., Ehleben, W., Porwol, T., Acker, H., Fandrey, J., Bauer, C., Gassmann, M. Oxygen tension modulates ß-globin switching in embryoid bodies.

Key Words: embryonic stem cells • hemoglobin • hypoxia-inducible factor • erythropoietin

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