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 demo nstrate that proliferation of embryonic multilineage hematopoietic progenit ors is also regulated by a hypoxia-mediated signaling pathway. This pathway requires HIF-1 (HIF-1 alpha/ARNT heterodimers) because Arnt(-/-) embryoid bodies fail to exhibit hypoxia-mediated progenitor proliferation. furthermo re, Arnt(-/-) embryos exhibit decreased numbers of yolk sac hematopoietic p rogenitors. 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 prolife ration or survival of hematopoietic precursors during development.