Manic fringe is not required for embryonic development, and fringe family members do not exhibit redundant functions in the axial skeleton, limb, or hindbrain

Abstract

Tight regulation of Notch pathway signaling is important in many aspects of embryonic development. Notch signaling can be modulated by expression of fringe genes, encoding glycosyltransferases that modify EGF repeats in the Notch receptor. Although Lunatic fringe (Lfng) has been shown to play important roles in vertebrate segmentation, comparatively little is known regarding the developmental functions of the other vertebrate fringe genes, Radical fringe (Rfng) and Manic fringe (Mfng). Here we report that Mfng expression is not required for embryonic development. Further, we find that despite significant overlap in expression patterns, we detect no obvious synergistic defects in mice in the absence of two, or all three, fringe genes during development of the axial skeleton, limbs, hindbrain, and cranial nerves.

Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions

“…Conceivably, this O-fucose glycan-modulated Notch signaling in the lymphoid development is compatible with Fringe-dependent regulation of Notch-ligand interaction shown by other studies, as the addition of O-fucose on Notch is a prerequisite of Fringe extension. Although O-fucose can activate Notch signaling independent of Fringe in Drosophila, 16 in mouse, 44 and in cell-based assays (J. Shin and J.B.L., unpublished data; July, 2010), whether this holds true in hematopoiesis awaits clarification in the future using Fringedeficient marrow progenitors. Pofut1 ϩ/Ϫ /FX Ϫ/Ϫ or Pofut1 ϩ/ϩ /FX Ϫ/Ϫ mice were maintained on fucose-supplemented chow (0.5% fucose weight/weight) until 8 weeks old and then maintained on standard chow without fucose supplementation for 1 month.…”

Hematopoietic stem cells: to be or Notch to be

“…30 Fringe modifications enhance the capacity of Notch to be activated by ligands of the Delta-like family (Dll1,Dll3, and Dll4) but reduce Notch activation by the Serrate/Jagged family of ligands (Jag1-2). 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.…”

Lunatic, Manic, and Radical Fringe Each Promote T and B Cell Development

“…In this paper, we investigate T and B cell development in mutant mice with inactivated Fng genes (20), including mice lacking a single Fng gene, all three Fng genes, or expressing only a single Fng (i. e. lacking two of the three Fng genes). While loss of Lfng may cause perinatal lethality, Lfng null homozygotes in a FVB/C57BL/6 mixed genetic background live for several months, although they are small, lack a tail, and are infertile (20–22).…”

“…While loss of Lfng may cause perinatal lethality, Lfng null homozygotes in a FVB/C57BL/6 mixed genetic background live for several months, although they are small, lack a tail, and are infertile (20–22). Deletion of Mfng or Rfng separately or together has no obvious effects on development or fertility (20, 23, 24). Here we show that DN T cell progenitors lacking expression of all three Fng genes ( Fng tKO) had reduced binding of Notch ligand DLL4 and reduced expression of the Notch targets Deltex1 and CD25.…”