Lfng and Dll3 cooperate to modulate protein interactions in cis and coordinate oscillatory Notch pathway activation in the segmentation clock

Bochter, Matthew S.; Servello, Dustin; Kakuda, Shinako; D'Amico, Rachel; Ebetino, Meaghan F; Haltiwanger, Robert S.; Cole, Susan E.

doi:10.1016/j.ydbio.2022.04.004

Cited by 11 publications

(12 citation statements)

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“…Requirements of Lfng for Notch ligand functions in thymic stroma were not addressed. However, there are cellular contexts in which effects of Fringe modification of canonical Notch ligands have been identified in other systems (for example (Bochter et al, 2022) and (Kadur Lakshminarasimha Murthy et al, 2018)), and it will be important to examine this issue and the role of each FNG during hematopoiesis in future.…”

Section: Fringe Glcnac-transferases In Lymphopoiesis and Myelopoiesismentioning

confidence: 99%

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Stanley

Tanwar

2022

Front. Mol. Biosci.

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Notch signaling via NOTCH1 stimulated by Delta-like ligand 4 (DLL4) is required for the development of T cells in thymus, and NOTCH2 stimulated by Notch ligand DLL1 is required for the development of marginal zone (MZ) B cells in spleen. Notch signaling also regulates myeloid cell production in bone marrow and is an essential contributor to the generation of early hematopoietic stem cells (HSC). The differentiation program in each of these cellular contexts is optimized by the regulation of Notch signaling strength by O-glycans attached to epidermal growth factor-like (EGF) repeats in the extracellular domain of Notch receptors. There are three major types of O-glycan on NOTCH1 and NOTCH2 - O-fucose, O-glucose and O-GlcNAc. The initiating sugar of each O-glycan is added in the endoplasmic reticulum (ER) by glycosyltransferases POFUT1 (fucose), POGLUT1/2/3 (glucose) or EOGT (GlcNAc), respectively. Additional sugars are added in the Golgi compartment during passage through the secretory pathway to the plasma membrane. Of particular significance for Notch signaling is the addition of GlcNAc to O-fucose on an EGF repeat by the Fringe GlcNAc-transferases LFNG, MFNG or RFNG. Canonical Notch ligands (DLL1, DLL4, JAG1, JAG2) expressed in stromal cells bind to the extracellular domain of Notch receptors expressed in hematopoietic stem cells and myeloid and lymphoid progenitors to activate Notch signaling. Ligand-receptor binding is differentially regulated by the O-glycans on Notch. This review will summarize our understanding of the regulation of Notch signaling in myeloid and lymphoid cell development by specific O-glycans in mice with dysregulated expression of a particular glycosyltransferase and discuss how this may impact immune system development and malignancy in general, and in individuals with a congenital defect in the synthesis of the O-glycans attached to EGF repeats.

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Section: Fringe Glcnac-transferases In Lymphopoiesis and Myelopoiesismentioning

confidence: 99%

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Stanley

Tanwar

2022

Front. Mol. Biosci.

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“…The applications of physics in other fields has been always a matter of interest and revolutionary results [28,39,40]. An application of prime interest is of the principles of a harmonic oscillator in complex bio-systems [41,42]. One such system is oscillations in proteins.…”

Section: Protein Oscillationsmentioning

confidence: 99%

Entropic Analysis of Protein Oscillations through Langevin Equations & Fokker-Planck Equations

Baughman

Sharma

2022

J. Hum. Earth Future

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Background: Protein oscillations have been one of the major highlights in the field of biophysics and bio-molecules. These oscillations can give us insights into complex bio-molecules and reveal their nature at a very fundamental level. They can also show us the dynamics involved in the functioning of bio-molecules through the nature of these oscillations. Method/Objective: In this article, we have described the basics of protein oscillations, giving a very fundamental approach to the physics of oscillations. We have also described some bio-systems in which protein oscillations play a vital role. In this article, we have used the Langevin equations and Fokker-Planck equations to describe the oscillation dynamics of proteins. Findings:Finally, we have shown the trend of an increase in the entropy of the oscillations by involving a perturbation term in the regular nature of oscillations. The entropy of protein oscillations is very important in understanding protein dynamics. Doi: 10.28991/HEF-SP2022-01-05 Full Text: PDF

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“…Dll4 has been shown to have a strong cis -inhibitory effect on Notch1 receptors which can partially override Dll1-mediated trans-activation in vitro using HeLa cells and Chinese Hamster Ovary cells ( Preuße et al, 2015 ). Another study, which also used immortalized HeLa cells in vitro , showed that Dll3 can act in cis , and potentiate the trans -activating capabilities of Dll1 ( Bochter et al, 2022 ). While trans and cis -regulation have been mechanistically demonstrated, it is still challenging to generalize the activating/inhibiting effects of different ligands observed in the above studies to particular tissue- or species-specific contexts.…”

Section: Introductionmentioning

confidence: 99%

“…For example, o-glucosylation and o-fucosylation of the Notch receptors are carried out by Protein O-Glucosyl Transferase (POGLUT) and Protein O-Fucosyl Transferase (POFUT) respectively in the trans-Golgi network ( Shi and Stanley, 2003 ; Acar et al, 2008 ). These modifications act as a base for N-Acetylglucosamination imparted by Notch signaling targets called the Fringe proteins which modulate the receptor’s ability to respond to ligands like Dll1 or Jag1 ( Kakuda and Haltiwanger, 2017 ; Bochter et al, 2022 ). Seemingly, both Dll1 and Dll3 also have these conserved residues, making them amenable to these modifications ( Bochter et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…These modifications act as a base for N-Acetylglucosamination imparted by Notch signaling targets called the Fringe proteins which modulate the receptor’s ability to respond to ligands like Dll1 or Jag1 ( Kakuda and Haltiwanger, 2017 ; Bochter et al, 2022 ). Seemingly, both Dll1 and Dll3 also have these conserved residues, making them amenable to these modifications ( Bochter et al, 2022 ). Expression of one of the Fringe proteins- Lunatic Fringe (Lfng) in a signal-sending cell (containing the trans-activating ligand Dll1) has been shown to attenuate Notch-activation in vitro using HEK293T and NIH3T3 cells ( Bochter et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Species-specific roles of the Notch ligands, receptors, and targets orchestrating the signaling landscape of the segmentation clock

Ramesh,

Chu

2024

Front. Cell Dev. Biol.

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Somitogenesis is a hallmark feature of all vertebrates and some invertebrate species that involves the periodic formation of block-like structures called somites. Somites are transient embryonic segments that eventually establish the entire vertebral column. A highly conserved molecular oscillator called the segmentation clock underlies this periodic event and the pace of this clock regulates the pace of somite formation. Although conserved signaling pathways govern the clock in most vertebrates, the mechanisms underlying the species-specific divergence in various clock characteristics remain elusive. For example, the segmentation clock in classical model species such as zebrafish, chick, and mouse embryos tick with a periodicity of ∼30, ∼90, and ∼120 min respectively. This enables them to form the species-specific number of vertebrae during their overall timespan of somitogenesis. Here, we perform a systematic review of the species-specific features of the segmentation clock with a keen focus on mouse embryos. We perform this review using three different perspectives: Notch-responsive clock genes, ligand-receptor dynamics, and synchronization between neighboring oscillators. We further review reports that use non-classical model organisms and in vitro model systems that complement our current understanding of the segmentation clock. Our review highlights the importance of comparative developmental biology to further our understanding of this essential developmental process.

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Lfng and Dll3 cooperate to modulate protein interactions in cis and coordinate oscillatory Notch pathway activation in the segmentation clock

Cited by 11 publications

References 79 publications

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Regulation of myeloid and lymphoid cell development by O-glycans on Notch

Entropic Analysis of Protein Oscillations through Langevin Equations & Fokker-Planck Equations

Species-specific roles of the Notch ligands, receptors, and targets orchestrating the signaling landscape of the segmentation clock

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