PubMed Health⌕ Search

Biomedical subjects

A Nichogiannopoulou

Publications and source records attributed to A Nichogiannopoulou.

9 recordsLinked to original sources
PubMed1999

Defects in hemopoietic stem cell activity in Ikaros mutant mice.

Here we provide evidence that the Ikaros family of DNA binding factors is critical for the activity of hemopoietic stem cells (HSCs) in the mouse. Mice homozygous for an Ikaros null mutation display a >30-fold reduction in long-term repopulation units, whereas mice homozygous for an Ikaros dominant negative mutation have no measurable activity. The defect in HSC activity is also illustrated by the ability of wild-type marrow to repopulate unconditioned Ikaros mutants. A progressive reduction in multipotent CFU-S(14) (colony-forming unit-spleen) progenitors and the earliest erythroid-restricted precursors (BFU-E [burst-forming unit-erythroid]) is also detected in the Ikaros mutant strains consistent with the reduction in HSCs. Nonetheless, the more mature clonogenic erythroid and myeloid precursors are less affected, indicating either the action of a compensatory mechanism to provide more progeny or a negative role of Ikaros at later stages of erythromyeloid differentiation. In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors flk-2 and c-kit is observed in the lineage-depleted c-kit(+)Sca-1(+) population that is normally enriched for HSCs and may in part contribute to the early hemopoietic phenotypes manifested in the absence of Ikaros.

Age Factors↗
PubMed1998

Ikaros in hemopoietic lineage determination and homeostasis.

Studies on the molecular mechanisms that control hemopoietic differentiation have focused on signaling cascades and nuclear effectors that drive this complex developmental system in a regulated fashion. Here we review the role of Ikaros, the founding member of a unique family of zinc finger transcription factors in this developmental process. Studies on an Ikaros null mutation have revealed an essential role for this factor in lymphoid cell fate determination and at subsequent branch points of the T cell differentiation pathway. Differences in the phenotypes of a null and a dominant negative (DN) Ikaros mutation provide insight into a regulatory network through which Ikaros proteins exert their effects in development. In addition a comparative analysis of the hemopoietic stem cell and precursor compartment resulting from the two Ikaros mutations reveals a profound yet not absolute requirement for Ikaros in the production and differentiation of these populations.

Animals↗
PubMed1997

Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage.

The transcription factor Ikaros is a major determinant of lymphocyte differentiation. Mice homozygous for an Ikaros dominant-negative (DN-/-) mutation lack all cells of lymphoid origin, including T, B, and natural killer (NK) cells. Mice homozygous for an Ikaros null allele lack B and NK cells but display specific defects in T lymphocytes. Nonetheless, both Ikaros mutant lines make an excess of monocytes and macrophages. Here we report that the production of subsets of antigen-presenting dendritic cells (DCs) is also defective. By constructing bone marrow chimeras, we demonstrate that the Ikaros-mediated defect in lymphocytes and DCs is intrinsic to their precursors and is not environment dependent. The selective defects in DCs manifested with the Ikaros null mutation suggest a tight linkage between development of T cells and CD8alpha+ DCs. The complete lack of DCs in the lymphoid organs of Ikaros DN-/- micke points to an essential role for the Ikaros gene family in the development of all DCs.

Animals↗
PubMed1996

Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.

Mice homozygous for an Ikaros null mutation display distinct defects in the development of fetal and adult lymphocytes. Fetal T lymphocytes, and fetal and adult B lymphocytes and their earliest progenitors are absent. Postnatally, hematopoietic stem cells give rise to thymocyte precursors that undergo aberrant differentiation into the CD4 lineage and clonal expansion. The lack of NK cells and some gamma delta T cell subsets and a large reduction in thymic dendritic APCs suggest that Ikaros is essential for establishing early branch points in the postnatal T cell pathway. The lymphoid defects detected in Ikaros null mice reveal critical molecular differences between fetal and postnatal hematopoietic progenitors that dictate their ability to give rise to T cells. These studies also establish Ikaros as a tumor suppressor gene acting during thymocyte differentiation. Phenotypic comparison of this null mutation with a severe dominant-negative Ikaros mutation identifies molecular redundancy in the postnatal hemolymphoid system.

Animals↗
PubMed1996

Natural killer cell development is blocked in the context of aberrant T lymphocyte ontogeny.

Over-expression of human or mouse CD3-epsilon transgenes profoundly disturbs T lymphocyte and natural killer (NK) cell development. One of these transgenic strains, termed tgepsilon26, displays a very early block in T lymphocyte and NK cell development. We showed previously that the absence of early thymocyte progenitors results in an abnormal thymic microenvironment. Due to this thymic defect, T cell development could not be restored by bone marrow (BM) transplantation in adult tgepsilon26 mice but could in fetal tgepsilon26 mice. Here we examine the effect of this abnormal thymic environment on NK cell development. We demonstrate that NK cell maturation in tgepsilon26 mice was reconstituted by BM derived from completely T cell-deficient mice, i.e. RAG-2(-/-) and TCRbeta x delta-/-, but not from wild-type mice. Moreover, tgepsilon26 mice transplanted with BM from partially T cell-deficient mice, i.e. TCRalpha-/-, TCRbeta-/- and TCRdelta-/- mice, did not reconstitute their NK cell compartment. We conclude from these studies that the thymic environment is not required for NK cell development, but that aberrantly educated alphabeta or gammadelta T lymphocytes can influence NK cell ontogeny. Furthermore, high serum levels of tumor necrosis factor (TNF) were detected in the vast majority of tgepsilon26 mice transplanted with BM cells derived from partially T cell-deficient mice, but never from tgepsilon26 mice transplanted with BM cells derived from completely T cell-deficient mice. The high levels of TNF may play an important role in the observed inhibition of NK cell development, since in vivo treatment with an anti-TNF antibody restored NK cell development.

Animals↗
PubMed1995

Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes.

T lymphocytes of the alpha/beta T-cell receptor (TCR) lineage mature in the thymus, where they undergo a series of differentiation, expansion and selection events. For normal T-cell ontogeny to occur, thymocytes must interact physically with cortical and medullary thymic stroma cells. In parallel, interactions of the thymic stromal cells with TCR-positive thymocytes are necessary for the development of the thymic medulla. Comparable requirements for the differentiation of the cortex have not been defined, however. Here we analyse mutant mouse strains to assess the function of early prothymocytes in the induction of the thymic cortex. We find that animals with a developmental block at the earliest stage of T-lineage commitment lack a functional thymic cortex. This abnormality could be corrected in fetal but not adult animals by transplantation of either fetal or adult wild-type haematopoietic stem cells. Thus a developmentally restricted interaction of fetal stromal cells with early prothymocytes is required for the induction of a cortical microenvironment. In addition, a normal thymic architecture is necessary for sustained T-cell ontogeny.

Aging↗
PubMed1995

Severe colitis in mice with aberrant thymic selection.

Tg epsilon 26 mice display an arrest very early in T cell development that has a profound effect on the architecture of thymic stromal cells. We have recently demonstrated that transplantation of wild-type bone marrow cells restores the thymic microenvironment of fetal but not adult Tg epsilon 26 mice. Here, we report that T cell-reconstituted adult Tg epsilon 26 mice develop a spontaneous wasting syndrome characterized by extensive inflammation of the colon, resembling human ulcerative colitis. Colitis in these animals was marked by substantial infiltration of the colon by activated thymus-derived CD4+ T cells. Importantly, bone marrow-transplanted Tg epsilon 26 mice previously engrafted with a fetal Tg epsilon 26 thymus did not develop colitis. These results suggest that T cells selected in an aberrant thymic microenvironment contain a population of cells able to induce severe colitis that can be prevented by T cells that have undergone normal thymic development.

Animals↗
PubMed1993

Early B cell development requires mu signaling.

In vitro studies with Abelson murine leukemia virus (AMuLV)-transformed murine pre-B cell lines demonstrated that wild-type mu but not mutant mu chains lacking the first constant domain (mu delta 1) can efficiently induce Ig light (L) chain gene rearrangement. Using antibodies against the cytoplasmic tail of the immunoglobulin co-receptor beta (Ig beta) chain we find mu, but not mu delta 1 chains associated with Ig beta. Since a heterodimer of surface-labeled proteins was co-precipitated with mu we conclude that only wild-type mu is associated with the Ig alpha/Ig beta co-receptor on the surface of pre-B cell lines. Mutant mu delta 1 chains achieve their surface expression by utilizing a glycophospholipid anchor. In vivo analysis of transgenic mice expressing either mu or mu delta 1 transgenes revealed the expected "normal" B cell development in the case of wild-type mu transgenic lymphocytes, but a block in differentiation of mu delta 1 transgenic lymphocytes. The maturation block occurs at the developmental transition of pre-B lymphocytes from the CD43/S7+, CD45R/B220low stage to the CD43/S7-, B220low/high stage in which the majority of L chain gene rearrangements occur. These results, together with the observed inability of the mu delta 1 chains to signal activation of L chain gene joining and to associate Ig alpha/Ig beta in pre-B cell lines suggests that signals mediated by the protein complex composed to mu/Ig alpha/Ig beta are crucial during differentiation of pre-B lymphocytes.

Abelson murine leukemia virus↗