Normal Immune System Development in Mice Lacking the Deltex-1 RING Finger Domain

Abstract

The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitment. Deltex-1 was also found to be highly expressed in germinal-center B cells. To investigate the physiological function of Deltex-1, we generated a mouse strain lacking the Deltex-1 RING finger domain, which is essential for its ubiquitin ligase activity. Deltex-1 ⌬/⌬ mice were viable and fertile. A detailed histological analysis did not reveal any defects in major organs. T-and B-cell development was normal, as were humoral responses against T-dependent and T-independent antigens. These data indicate that the Deltex-1 ubiquitin ligase activity is dispensable for mouse development and immune function. Possible compensatory mechanisms, in particular those from a fourth Deltex gene identified during the course of this study, are also discussed.

T Cells Develop Normally in the Absence of both Deltex1 and Deltex2

“…In initial studies, we examined mice that were deficient in only Deltex1, and we were unable to detect any defects in thymocyte maturation in these mice. Our results are consistent with those published by Storck et al (74) and extend their findings in several ways. First, we targeted the first coding exon of Deltex1, to be certain that Deltex1 expression is completely eliminated.…”

“…Deltex mutants share some of the phenotypic characteristics resulting from mutations in key components of the Notch pathway and exacerbate Notch loss-of-function phenotypes (23). Three mammalian homologues of the Drosophila Deltex gene have now been identified (37,74) (the Deltex1, Deltex2, and Deltex4 genes), which code for a family of cytoplasmic proteins that contain three structural domains. Domain I contains two WWE repeats (6) that have been shown to physically interact with the Notch ankyrin domains (16,50,84).…”

Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter

“…30 Deltex1 partially inhibits the transactivation of an RBP-J-dependent luciferase reporter by NotchIC in several human and murine cells, including B (BJAP) and T (Jurkat) cells. However, a recent report 38 showed that the numbers of ectopic B cells in the thymus remained unchanged and B-cell development in the spleen was unaltered in Deltex1 mutant mice. Hence, conclusions of in vivo organ culture and biochemical studies by Izon et al 30 are still controversial.…”

The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation

“…In a previous screen for genes differentially expressed in B cells undergoing immunoglobulin hypermutation, two genes have emerged as interesting candidates: the RING finger ubiquitin ligase Deltex-1, and KLHL6 (9). A role for Deltex-1 in the immune system has recently been excluded based on a detailed analysis of Deltex-1-deficient mice (27). With regard to KLHL6, expression of this gene in lymphoid tissues (9), specifically in all stages of B-cell development (Fig.…”