Control of cell proliferation is a central theme in development. How the number of divisions a cell undergoes during organ formation is limited is not well understood, but it is known that the mechanisms controlling proliferation are conserved in humans and Drosophila. And most genes essential for the formation and maturation of the Drosophila lymph gland and hemocytes are conserved in humans. Pathways such as Toll-NF:B, JAK/STAT, Notch, and Ras/Raf regulate hematopoiesis in vertebrates and lymph gland development in flies. A gene we have identified controls the number of divisions a cell undergoes. Its protein (Zfrp8) is >50% similar to the human protein (PDCD2). The most obvious phenotype of fly zfrp8/PDCD2 mutants is a massive overgrowth of the hematopoietic organ, the lymph gland, accompanied by a delay in larval development. We have found that zfrp8 regulates lymph gland growth by controlling cell proliferation and not apoptosis. Our results suggest that zfrp8 regulates Stat levels in Drosophila. Loss of zfrp8 results in a similar phenotype to gain-of-function mutations in the JAK/STAT pathway. PDCD2 appears to be involved in human hematopoiesis and is present in human tissues in two major forms. In bone marrow we detect a larger form of the protein that is enriched in a fraction containing stem cells. A smaller form of the protein is present in barely detectable amounts in white blood cells. In both the bone marrow and blood of leukemia patients, high levels of the smaller form of PDCD2 are present. We plan to define the role of zfrp8 in Drosophila in normal lymph gland and hemocyte development, and in growth of other tissues and to identify its molecular function. Using a variety of approaches we will search for additional genes functioning with zfrp8. Further, we will define the gene products of PDCD2 in vertebrates, and will investigate their function in cell proliferation in human hematopoiesis using in vitro cell differentiation of blood stem cells and tissue culture cells.
Blood cell development in our model, the fruit fly, is similar in humans, and many of the genes in both humans and fruit flies having to do with blood development are also involved in blood cancers. We have identified a new gene, zfrp8 that if absent, results in flies that show an enormous over-proliferation of blood cells. In humans the same gene is called PDCD2. At least two forms of the PDCD2 protein are present in humans. In bone marrow there is a larger form and in white blood cells we can barely detect a smaller form. We propose a thorough study of how PDCD2/Zfrp8 regulates blood cell formation in flies and to use our findings as a guide to investigate the role of this crucial gene in human blood formation.
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