Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis

Murthy, Preetish Kadur Lakshminarasimha; Srinivasan, Tara; Bochter, Matthew S.; Rui, Xiaoting; Varanko, Anastasia Kristine; Tung, Kuei-Ling; Semerci, Fatih; Xu, Keli; Maletić-Savatić, Mirjana; Cole, Susan E.; Shen, Xiling

doi:10.7554/elife.35710

Cited by 24 publications

(17 citation statements)

References 50 publications

(82 reference statements)

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“…Lfng is expressed in NEBs rather than in the NEB-associated CCs, which activates Notch signaling (Xu et al, 2010b; Xu et al, 2010a). This is reminiscent of the developing intestinal epithelium where Fringe is expressed in the ligand-presenting cells to promote Notch activity in the neighboring cells (Kadur Lakshminarasimha Murthy et al, 2018). There is currently no evidence that these proteins influence epithelial Notch signaling in the developing lung epithelium (van Tuyl et al, 2005; Xu et al, 2010b; Xu et al, 2010a).…”

Section: Discussionmentioning

confidence: 99%

Jagged and Delta-like ligands control distinct events during airway progenitor cell differentiation

Stupnikov

Yang

Mori

et al. 2019

eLife

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Notch signaling regulates cell fate selection during development in multiple organs including the lung. Previous studies on the role of Notch in the lung focused mostly on Notch pathway core components or receptor-specific functions. It is unclear, however, how Jagged or Delta-like ligands collectively or individually (Jag1, Jag2, Dll1, Dll4) influence differentiation of airway epithelial progenitors. Using mouse genetic models we show major differences in Jag and Dll in regulation and establishment of cell fate. Jag ligands had a major impact in balancing distinct cell populations in conducting airways, but had no role in the establishment of domains and cellular abundance in the neuroendocrine (NE) microenvironment. Surprisingly, Dll ligands were crucial in restricting cell fate and size of NE bodies and showed an overlapping role with Jag in differentiation of NE-associated secretory (club) cells. These mechanisms may potentially play a role in human conditions that result in aberrant NE differentiation, including NE hyperplasias and cancer.

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Section: Discussionmentioning

confidence: 99%

Jagged and Delta-like ligands control distinct events during airway progenitor cell differentiation

Stupnikov

Yang

Mori

et al. 2019

eLife

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“…DLL4 is a Notch ligand that is essential for the homeostasis of stem and progenitor cells and the simultaneous inactivation of Dll1 and Dll4, resulting in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of stem cells (SCs) (Olfm4(+), Lgr5(+) and Ascl2(+)) [ 21 ]. Another study showed that Dll1 and Dll4 could be regulated by Fringe proteins, such as Lfng and Rfng; the latter is enriched in Paneth cells, and the former is mainly expressed in the villus; they promote cell surface expression of DLL1 and DLL4, further contributing to Lgr5+ ISCs self-renewal [ 25 ]. The influence of PCs on intestinal stem cells is similar to that of in vitro organoids.…”

Section: Paneth Cells Mediate Intestinal Stem Cell Renewal and Regenementioning

confidence: 99%

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Mei

2020

Stem Cell Res Ther

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Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.

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“…DLL1 has four EGF repeats that receive O-fucose but DLL1 expressed in Pofut1 -null presomitic mesoderm or mouse embryo fibroblasts was localized to the cell surface and stimulated Notch signalling [87]. By contrast, experiments with intestinal cells showed that Paneth cells have slightly reduced cell surface expression of DLL1 and DLL4 when RFNG is absent, and cells from cultured intestinal organoids have reduced DLL1 on the cell surface after knockdown of Lfng [89]. Lfng knockout mice have reduced DLL1 and DLL4 on the surface of goblet cells, whose numbers are increased due to a reduction in Notch signalling in the absence of Lfng [89].…”

Section: O-fucose Glycansmentioning

confidence: 99%

“…By contrast, experiments with intestinal cells showed that Paneth cells have slightly reduced cell surface expression of DLL1 and DLL4 when RFNG is absent, and cells from cultured intestinal organoids have reduced DLL1 on the cell surface after knockdown of Lfng [89]. Lfng knockout mice have reduced DLL1 and DLL4 on the surface of goblet cells, whose numbers are increased due to a reduction in Notch signalling in the absence of Lfng [89]. Thus, depending on cellular context, cell surface expression of Notch ligands may be promoted by Fringe modification.…”

Section: O-fucose Glycansmentioning

confidence: 99%

“…Fringe regulates Notch signalling based on differential interactions between Notch modified by Fringe with Delta-like versus Jagged Notch ligands. Fringe may also promote the cell surface expression of Delta-like ligands [89]. A role for the addition of Gal to Fringe-modified Notch receptors was observed in B4galt1 null embryos which exhibit reduced expression of several Notch target genes during somitogenesis [104].…”

Section: O-fucose Glycansmentioning

confidence: 99%

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Multiple roles for O‐glycans in Notch signalling

Varshney

Stanley

2018

FEBS Letters

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Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine-tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O-fucose, O-GlcNAc and O-glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O-glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O-glycosylation in regulating Notch signalling. O-glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O-glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O-glycans on Notch receptors and their differential effects on Notch signalling.

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Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis

Cited by 24 publications

References 50 publications

Jagged and Delta-like ligands control distinct events during airway progenitor cell differentiation

Jagged and Delta-like ligands control distinct events during airway progenitor cell differentiation

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Multiple roles for O‐glycans in Notch signalling

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