The long term objective of this proposal is to delineate the cellular and molecular mechanisms that mediate differentiation and homeostasis in the mouse hemopoietic system. In particular, we would like to determine the role of the regulatory gene Ikaros in the events that control lineage commitment in the hemolymphopoietic system. Complete an partial inactivation of the Ikaros gene in the mouse germ line have a wide range of effects, that range from severe combined immunodeficiencies to leukemias/lymphomas. The high degree of conservation of the Ikaros gene between mouse and human, strongly suggest its involvement in similar regulatory pathways in the human hemolymphopoietic system. In this proposal we intend to analyse the hemopoietic defects in mice homozygous for a deletion in the DNA binding domain of the Ikaros gene (D.B-/-). Ikaros D.B-/- mice lack all three lymphoid lineages and their earliest defined progenitors. Bone marrow hypocellularity and extramedullary hemopoiesis in the spleen with increased production of erythroid and myeloid progenitors, are hallmarks of the Ikaros D.B-/- phenotype. In addition, the maturation of myeloid progenitors to terminally differentiated granulocytes is impaired. The cell autonomous nature of the hemolymphopoietic defects in the Ikaros D.B-/- mice will be studied in vivo in competitive repopulation assays and in vitro in differentiation culture systems. Lineage interactions and the role of the microenvironment in the development of the hemolymphopoietic system will be addressed in reconstitution assays in Ikaros D.B-/- mice. The usefulness of the Ikaros D.B-/- mouse as a transplantation host in studying effector functions in the immune system, will be established. A comparative molecular analysis between Ikaros D.B-/- and wild type hemopoietic populations will be performed to identify genetic targets for the Ikaros gene affected by the mutation. The proposed studies, on the developmental and molecular characterization of hemopoietic populations in Ikaros D.B-/- mice, will permit a bird's view of the cellular and molecular regulatory networks that underlie the complex hierarchy of the hemopoietic system.
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