Selective Defects in the Development of the Fetal and Adult Lymphoid System in Mice with an Ikaros Null Mutation

Abstract

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.

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

“…Additionally, leukemogenesis induced by Ikaros deficiency is similar in phenotype to that induced by constitutively active Notch1. 33,47,48 Kathrein et al 41 contended that Ikaros deficiency results in de-repression of Hes1 in vivo and calculated that activating mutations of Notch1 in Ikaros-deficient cells further increase the expression of Hes1. In our study, the Hes1 level in TLs with mutations in both Ikaros and Notch1 was increased significantly compared to TLs harboring either mutation alone, suggesting that cooperative mutations advance Notch signaling via Hes1.…”

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

“…Ikaros had been previously targeted and analysis of a null allele, a hypomorphic allele, and a dominant negative allele had shown that Ikaros was involved in lymphocyte, B cell, and natural killer cell development (Georgopoulos et al, 1994;Wang et al, 1996;Kirstetter et al, 2002). The ENU-induced allele, Ikaros plastic , showed defects in the formation of additional blood cell types including erythrocytes, granulocytes, and macrophages.…”

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

“…In addition to defects in B cell development, Ik-null and Ik L/L mice develop T cell leukemia with 100% penetrance [1,2]. This phenotype is also observed in a third genetically engineered Ikaros mutant mouse line in which targeted deletion of exons 3 and 4 of the Ikaros gene results in high-level expression of non-DNAbinding Ikaros proteins from the targeted allele [3,4].…”

“…It is expressed at high levels at all stages of B cell development as well as in the mature B cell, providing circumstantial evidence that it plays a role in regulation of mature B cell function. Mice engineered to lack Ikaros (Ik-null mice) display a complete block in B cell development, making study of the role of Ikaros in B cell development and function difficult to impossible in this system [1]. In a second genetically engineered line of mice, Ik L/L mice, a b-galactosidase reporter gene was inserted into exon 2 of the Ikaros locus [2].…”