The concept that the hematopoietic and endothelial lineages of the early yolk sac arise from a common progenitor, the hemangioblast, was put forth almost a century ago. Using the in vitro differentiation of embryonic stem (ES) cells as a model of yolk sac hematopoiesis, progenitors with characteristics of the hemangioblast have been identified. Studies focusing on intra-embryonic hematopoietic development in the AGM region of the fetus, as well as those which have analyzed the progeny of single adult bone marrow cells in models of hematopoietic repopulation and angiogenesis have provided evidence that hemangioblasts may also exist in fetal and adult life. The notion that the hemangioblast exists at stages of development beyond the yolk sac suggests that such progenitors could represent the primordial stem cells of the hematopoietic and endothelial lineages and function in a pivotal role in the maintenance of the blood cell and vascular systems in the adult. The overall goals of this proposal are to define the origins of the hemangioblast at different developmental stages, to determining its relationship to the long-term repopulating stem cell and to elucidate the molecular programs that regulate its establishment, growth and differentiation. In the first aim of this proposal, the early yolk sac, the fetal P-Sp/AGM and the adult bone marrow will be analyzed for the presence of progenitors with hemangioblast characteristics. These studies should provide detailed information on the presence of such progenitors and their developmental potential. The focus of the second aim of the proposal is to determine if different subpopulations of mesoderm generate hemangioblasts that represent distinct hematopoietic programs. The findings from these experiments will provide new insights into the origins of the hematopoietic lineages found in the yolk sac and the embryo proper. The final aim of the proposal will investigate the molecular regulation of the hemangioblast and focus on the role of Epo/EpoR, scl/tal-1 and three newly identified genes in this developmental process. The outcome of these studies should provide new and important information on the origins of the hematopoietic and vascular lineages in embryonic, fetal and adult life and on the mechanisms that regulate the earliest commitment steps in their development. These findings will lead to a better understanding of the regulation of stem cells of the hematopoietic and vascular lineages that could ultimately lead to potential new therapies for blood cell disorders such as leukemia and anemia and for diseases associated with the vascular system including cardiovascular diseases. [unreadable] [unreadable] [unreadable]