Lunatic Fringe Controls T Cell Differentiation through Modulating Notch Signaling

Abstract

T cells differentiate from bone marrow-derived stem cells by expressing developmental stage-specific genes. We here searched arrays of genes that are highly expressed in mature CD4−CD8+ (CD8 single-positive (SP)) T cells but little in CD4+CD8+ (double-positive (DP)) cells by cDNA subtraction. Lunatic fringe (Lfng), a modulator of Notch signaling, was identified to be little expressed in DP cells and highly expressed in CD8SP T cell as well as in CD4−CD8− (double-negative (DN)) and mature CD4+CD8− (CD4SP) T cells. Thus, we examined whether such change of expression of Lfng plays a role in T cell development. We found that overexpression of Lfng in Jurkat T cells strengthened Notch signaling by reporter gene assay, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cells development due to the defective transition from CD44+CD25− stage to subsequent stage in DN cells. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggested that the physiological high expression of Lfng in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling. Shutting down the expression of Lfng in DP cells may have a physiological role in promoting DP cells differentiation toward mature SP cells.

Dendritic cell-mediated NK cell activation is controlled by Jagged2–Notch interaction

“…Alternatively, the interaction of Notch and Notch ligands might be controlled by modifying the sugar pattern of Notch by fringe genes. The fringe-mediated addition of N-acetylglucosamine to o-fucose moieties on Notch could change the ligand sensitivity of Notch (22)(23)(24). In support of this, we have observed that NK cells express fringe genes (data not shown).…”

Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros

“…9C). We suggest that rfng overexpression caused ectopic pronephrogenesis by promoting Notch signalling, as has been described in other systems (Hicks et al, 2000;Tsukumo et al, 2006). Promotion of pronephric Notch signalling activates wnt4 expression, the protein product can be secreted in more distal positions than those found normally, thus producing ectopic proximal pronephros cell fates in distal regions.…”

“…In conclusion, Rfng promotes formation of the proximal pronephros and suppresses distal pronephrogenesis. In vertebrates, Fringe proteins promote Notch-ligand interactions (Haines and Irvine, 2003;Hicks et al, 2000;Tsukumo et al, 2006). We have shown that Wnt-4 acts downstream of Notch signalling (see above), thus we wished to confirm that Rfng also acted upstream of Wnt-4.…”

“…However, Notch-ICD-independent pathways are known to exist and are being realised as an important part of the overall signal transmitted by Notch-ligand interactions (Brennan and Gardner, 2002;Bush et al, 2001;Karsan, 2008). Unlike injection of notch-ICD mRNA, rfng overexpression would probably have a more global effect on Notch signalling because vertebrate Fringe proteins promote Notch-ligand interactions rather than one specific aspect of Notch signal transduction (Hicks et al, 2000;Tsukumo et al, 2006). Thus, we suggest that Notch-ICD-independent pathways have a role in development of the proximal pronephros.…”

Hematopoietic stem cells: to be or Notch to be

“…31 Although some studies suggest that knockout mutants for all 3 Fringes (in a specific genetic background) do not display more developmental malformations than single mutants for Lunatic Fringe, 32 it is well established that different Fringe homologs modulate particular Notch-mediated biologic processes in a specific manner, [33][34][35] such is the case of Lunatic Fringe in the hematopoietic lineage commitment and differentiation. [36][37][38][39] Another modification involving the extracellular domain of the Notch receptor is its O-glucosylation mediated by the O-glucosyltransferase (Poglut), Rumi. 40 However, the biochemical effects of this modification are mainly unknown, but it has been suggested that it might regulate the proper folding of Notch that is required for its efficient activation.…”