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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033062-08
Application #
6169714
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ridge, John P
Project Start
1993-05-01
Project End
2001-12-14
Budget Start
2000-05-01
Budget End
2001-12-14
Support Year
8
Fiscal Year
2000
Total Cost
$247,502
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Yoshida, Toshimi; Landhuis, Esther; Dose, Marei et al. (2013) Transcriptional regulation of the Ikzf1 locus. Blood 122:3149-59
Yoshida, Toshimi; Ng, Samuel Yao-Ming; Georgopoulos, Katia (2010) Awakening lineage potential by Ikaros-mediated transcriptional priming. Curr Opin Immunol 22:154-60
Koipally, J; Georgopoulos, K (2000) Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity. J Biol Chem 275:19594-602
Koipally, J; Renold, A; Kim, J et al. (1999) Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. EMBO J 18:3090-100
Nichogiannopoulou, A; Trevisan, M; Neben, S et al. (1999) Defects in hemopoietic stem cell activity in Ikaros mutant mice. J Exp Med 190:1201-14
Koipally, J; Kim, J; Jones, B et al. (1999) Ikaros chromatin remodeling complexes in the control of differentiation of the hemo-lymphoid system. Cold Spring Harb Symp Quant Biol 64:79-86
Kelley, C M; Ikeda, T; Koipally, J et al. (1998) Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr Biol 8:508-15
Morgan, B; Sun, L; Avitahl, N et al. (1997) Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J 16:2004-13
Wu, L; Nichogiannopoulou, A; Shortman, K et al. (1997) Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity 7:483-92
Sun, L; Liu, A; Georgopoulos, K (1996) Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J 15:5358-69

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