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Ikaros Regulates Notch Target Gene Expression in Developing Thymocytes¹

Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Both Ikaros and Notch are essential for normal T cell development. Collaborative mutations causing a reduction in Ikaros activity and an increase in Notch activation promote T cell leukemogenesis. Although the molecular mechanisms of this cooperation have been studied, its consequences in thymocyte development remain unexplored. In this study, we show that Ikaros regulates expression of a subset of Notch target genes, including Hes1, Deltex1, pTa, Gata3, and Runx1, in both Ikaros null T cell leukemia lines and Ikaros null primary thymocytes. In Ikaros null leukemia cells, Notch deregulation occurs at both the level of Notch receptor cleavage and expression of Notch target genes, because re-expression of Ikaros in these cells down-regulates Notch target gene expression without affecting levels of intracellular cleaved Notch. In addition, abnormal expression of Notch target genes is observed in Ikaros null double-positive thymocytes, in the absence of detectable intracellular cleaved Notch. Finally, we show that this role of Ikaros is specific to double-positive and single-positive thymocytes because derepression of Notch target gene expression is not observed in Ikaros null double-negative thymocytes or lineage-depleted bone marrow. Thus, in this study, we provide evidence that Ikaros and Notch play opposing roles in regulation of a subset of Notch target genes and that this role is restricted to developing thymocytes where Ikaros is required to appropriately regulate the Notch program as they progress through T cell development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health (R01 CA104962-01A1) awarded to S. Winandy. S. Chari was supported by The Cellular and Molecular Basis of Disease Training Grant, funded by the National Institutes of Health (T32 NIH T32 GM08061).

² Address correspondence and reprint requests to Dr. Susan Winandy, Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 320 E. Superior Street, Morton 6-639, Chicago, IL 60611. E-mail address: s-winandy{at}northwestern.edu

³ Abbreviations used in this paper: ICN, intracellular cleaved Notch; DN, double-negative; DP, double-positive; MAML, Mastermind-like; BGS, bovine growth serum; Pen-Strep, penicillin-streptomycin; HD, heterodimerization domain; PEST, Proline, Glutamine, Serine, and Threonine-rich domain; qRT-PCR, quantitative real-time RT-PCR; T-ALL, T-acute lymphoblastic leukemia; GSI, -secretase inhibitor; BM, bone marrow; RBP-J, recombination signal binding protein for immunoglobulin J; MSCV, murine stem cell virus.

This article has been cited by other articles:

				J. A. Urban, W. Brugmann, and S. Winandy Cutting Edge: Ikaros Null Thymocytes Mature into the CD4 Lineage with Reduced TCR Signal: A Study Using CD3{zeta} Immunoreceptor Tyrosine-Based Activation Motif Transgenic Mice J. Immunol., April 1, 2009; 182(7): 3955 - 3959. [Abstract] [Full Text] [PDF]