In mammals, the continuous production of hematopoietic cells (HCs) is sustained by a small number of hematopoietic stem cells (HSCs) residing in the bone marrow. Early HSC activity arises in the aorta-gonad mesonephros region, within cells localized to the ventral floor of the major blood vessels, suggesting that the first HSCs may be derived from cells capable of giving rise to the hematopoietic system and to the endothelial cells of the vasculature. TIE1 (TIE) and TIE2 (TEK) are related receptor tyrosine kinases with an embryonic expression pattern in endothelial cells, their precursors, and HCs, suggestive of a role in the divergence and function of both lineages. Indeed, gene targeting approaches have shown that TIE1, TIE2, and ligands for TIE2, the angiopoietins, are essential for vascular development and maintenance. To explore possible roles for these receptors in HCs, we have examined the ability of embryonic cells lacking both TIE1 and TIE2 to contribute to developmental and adult hematopoiesis by generating chimeric animals between normal embryonic cells and cells lacking these receptors. We show here that TIE receptors are not required for differentiation and proliferation of definitive hematopoietic lineages in the embryo and fetus; surprisingly, however, these receptors are specifically required during postnatal bone marrow hematopoiesis.A close cell lineage relationship between hematopoietic cells (HCs) and endothelial cells (ECs) has long been recognized (1, 2). During embryogenesis, both cell types emerge in a spatially and temporally tightly linked manner. In the yolk sac of the mouse embryo, primitive erythrocytes differentiate juxtaposed with EC precursors from extraembryonic mesoderm by embryonic day (E) 7.5, suggestive of origin from a common cellular precursor known as the hemangioblast. A second wave of hematopoiesis is initiated in the embryo around E10-E11, when adult-type (definitive) hematopoietic stem cells (HSCs) arise in the aorta gonad mesonephros (AGM) region in close association with the ventral portion of the dorsal aorta and umbilical and vitelline arteries (3). Fate mapping studies in the chick demonstrated that the ECs and HCs that form the ventral floor of the dorsal aorta share a common cellular origin in the splanchnopleural mesoderm (4), and the para-aortic splanchnopleure (P-Sp) of the mouse contains the progenitors of cells that are capable of long-term reconstitution (5). Little is known regarding the in vivo signaling mechanisms that assign both vascular and HSC properties to these anatomically localized mesodermal progenitors.By E11-E12, definitive HSCs leave the AGM region and colonize the fetal liver (FL) (6), where they proliferate and produce differentiated progeny that are released into the circulation, as well as lymphoid progenitors that seed the fetal thymus and spleen (7). The FL is the main hematopoietic organ until the end of gestation; after E15, HSCs migrate to and seed the bone marrow (BM) (8,9). In contrast to the migratory nature of fetal HSCs, adult ...