Notch-Regulated Ankyrin-Repeat Protein Inhibits Notch1 Signaling: Multiple Notch1 Signaling Pathways Involved In T Cell Development

Abstract

We have characterized the function of Notch-regulated ankyrin-repeat protein (Nrarp) in mouse cell lines and in hematopoietic stem cells (HSCs). Nrarp overexpression is able to block Notch-induced activation of CBF-1. In AKR1010 thymoma cells, Nrarp overexpression blocks CBF-1-dependent transcriptional activation of Notch-responsive genes and inhibits phenotypic changes associated with Notch activation. Enforced expression of Nrarp in mouse HSCs results in a profound block in T lineage commitment and progression through early stages of thymocyte maturation. In contrast, Deltex-1 overexpression in HSCs can also block T lineage commitment but not progression through the early double negative stages of thymocyte maturation. The different effects of Deltex-1 and Nrarp overexpression suggest that alternate Notch signaling pathways mediate T vs B lineage commitment and thymocyte maturation.

Regulation of innate and adaptive immunity by Notch

“…By contrast, the constitutive expression of active forms of Notch induced ectopic T cell development and suppressed B cell development in the bone marrow 12 . Since then, multiple studies, including studies interfering with Notch signalling by transgenic expression of Notch modulators (such as Fringe proteins, Deltex 1 and Notchregulated ankyrin repeat-containing protein (NRARP)) or studies expressing dominant-negative forms of the transcriptional co-activator Mastermind-like protein 1 (MAML1), have confirmed the original findings [13][14][15][16] . This led to a model in which Notch 1 ensures T cell lineage commitment by inhibiting the other multiple cell-fate potentials of thymus-seeding cells, including myeloid cell and B cell potential, as well as conventional DC and plasmacytoid DC potential [17][18][19][20] (FIG.…”

The Notch signaling pathway: Transcriptional regulation at Notch target genes

“…NRARP was first discovered in Xenopus and is a small 114 a.a. ankyrin-repeat containing protein [24]. NRARP is not only a direct Notch target gene [112] but interacts physically with NICD and blocks Notch-mediated transactivation and T lineage commitment [113,114]. A similar observation was described for Deltex-1 [115].…”

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…56 The Notch pathway is active in and necessary for T-cell development in the earliest thymocyte populations, 57,58 but has also been implicated in later stages of T-cell development, mostly in the DN to DP transition. [59][60][61][62][63] Furthermore, mice in which Notch1 was deleted after the T/B-fate choice (Lck-cre  Notch1 lox/lox ) show a complex phenotype which suggest that Notch1 contributes to both V to DJ rearrangement of the TCRB locus as well as to the physical elimination of cells that fail b-selection. 64 There are conflicting data on a function of Notch signaling in promoting ab-lineage T-cell development at the expense of gd T cells [64][65][66] and in the selection between CD4 and CD8 SP thymocytes.…”