Multilineage embryonic hematopoiesis requires hypoxic ARNT activity.
Although most cells undergo growth arrest during hypoxia, endothelial cells and placental cytotrophoblasts proliferate in response to low O(2). We demonstrate that proliferation of embryonic multilineage hematopoietic progenitors is also regulated by a hypoxia-mediated signaling pathway. This pathway requires HIF-1 (HIF-1alpha/ARNT heterodimers) because Arnt(-/-) embryoid bodies fail to exhibit hypoxia-mediated progenitor proliferation. Furthermore, Arnt(-/-) embryos exhibit decreased numbers of yolk sac hematopoietic progenitors. This defect is cell extrinsic, is accompanied by a decrease in ARNT-dependent VEGF expression, and is rescued by exogenous VEGF. Therefore, "physiologic hypoxia" encountered by embryos is essential for the proliferation or survival of hematopoietic precursors during development.
Adelman
D M
DM
Department of Pathology, and the Howard Hughes Medical Institute (HHMI), University of Chicago, Chicago, Illinois 60637, USA.
Maltepe
E
E
Simon
M C
MC
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002454:Cell Differentiation; D015687:Cell Hypoxia; D019070:Cell Lineage; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics; D004921:Erythropoietin / Q000235:genetics; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D013234:Stem Cells; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C497396:ARNT protein, human; C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator