Multilineage embryonic hematopoiesis requires hypoxic ARNT activity

Abstract

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-1␣/ 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 ARNTdependent 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. Received July 9, 1999; revised version accepted August 17, 1999. Low O 2 tension (hypoxia) is a condition commonly associated with pathology. Mammals adapt to hypoxia on an organismal level by increasing expression of erythropoietin (EPO) resulting in increased red blood cell production (Semenza et al. 1991), and vascular endothelial growth factor (VEGF) to promote increased vascularization of affected tissues (Shweiki et al. 1992;Forsythe et al. 1996). On a cellular level, mammals adapt to decreased O 2 by increasing expression of glycolytic enzymes (Bunn and Poyton 1996;Semenza et al. 1996;Wenger and Gassmann 1997) and glucose transporters (Bashan et al. 1992) for increased anaerobic respiration.Whereas the growth and division of many cell types is suppressed until O 2 tensions return to normoxic levels (20% O 2 ) (Graeber et al. 1996;Carmeliet et al. 1998), certain cell types must grow and proliferate in response to decreased O 2 . These include placental cytotrophoblasts (Genbacev et al. 1997), which form the maternalfetal interface in the womb (Rodesch et al. 1992;Fischer and Bavister 1993), and vascular endothelial cells, which proliferate to form new capillaries in hypoxic tissues (Phillips et al. 1995). A critical component of the hypoxic response machinery is the bHLH-PAS transcription factor complex hypoxia-inducible factor 1 (HIF-1). HIF-1 activates the expression of genes involved in a broad spectrum of adaptive responses to oxygen deprivation ranging from basic metabolism to angiogenesis and erythropoiesis (Bunn and Poyton 1996;Wenger and Gassmann 1997;Maltepe and Simon 1998), and may impact cell-cycle regulation by interacting with and stabilizing the tumor supressor protein p53 . HIFs are obligate heterodimers comprised of the bHLH-PAS proteins HIF-1␣ (or HIF-2␣) and the arylhydrocarbon receptor nuclear translocator (ARNT; HIF-1␤). All components are constitutively expressed, although HIF-1␣ and HIF-2␣ are quickly degraded under normoxia and stabilized under hypoxia (Salceda and Caro 1997;Wiesener et al. 1998), allowing for HIF activity specifically under hypoxic conditions.Before establishment of a circulatory system capable of delivering oxygenated blood to the embryo, mammalian development occur...

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

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Identification of pleiotropic genes and gene sets underlying growth and immunity traits: a case study on Meishan pigs

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