scholarly journals Notch Signaling Regulation in Autoinflammatory Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8847
Author(s):  
Rossella Gratton ◽  
Paola Maura Tricarico ◽  
Adamo Pio d'Adamo ◽  
Anna Monica Bianco ◽  
Ronald Moura ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Notch Pathway ◽  
Autoinflammatory Diseases ◽  
Cellular Processes ◽  
Core Components

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.

Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1154-1162 ◽  
Author(s):  
Wei Zheng ◽  
Tuomas Tammela ◽  
Masahiro Yamamoto ◽  
Andrey Anisimov ◽  
Tanja Holopainen ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Notch Pathway ◽  
Lymphatic Vessels ◽  
Soluble Form ◽  
Fibrin Gel ◽  
3 Dimensional ◽  
Endothelial Growth Factor

Abstract Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.

Abstract 3380: Acetylation-dependent Regulation Of Notch1 Signaling In Endothelial Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Virginia Guarani ◽  
Franck Dequiedt ◽  
Andreas M Zeiher ◽  
Stefanie Dimmeler ◽  
Michael Potente
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Trichostatin A ◽  
Notch Pathway ◽  
Dependent Manner ◽  
Class Iii ◽  
Cell Fate Decisions ◽  
Knock Down

The Notch signaling pathway is a versatile regulator of cell fate decisions and plays an essential role for embryonic and postnatal vascular development. As only modest differences in Notch pathway activity suffice to determine dramatic differences in blood vessel development, this pathway is tightly regulated by a variety of molecular mechanisms. Reversible acetylation has emerged as an important post-translational modification of several non-histone proteins, which are targeted by histone deacetylases (HDACs). Here, we report that specifically the Notch1 intracellular domain (NICD) is itself an acetylated protein and that its acetylation level is tightly regulated by the SIRT1 deacetylase, which we have previously identified as a key regulator of endothelial angiogenic functions during vascular growth. Coexpression of NICD with histone acetyltransferases such as p300 or PCAF induced a dose- and time-dependent acetylation of NICD. Blocking HDAC activity using the class III HDAC inhibitor nicotinamid (NAM), but not the class I/II HDAC inhibior trichostatin A, resulted in a significant increase of NICD acetylation suggesting that NICD is targetd by class III HDACs for deacetylation. Among the class III HDACs with deacetylase activity (SIRT1, 2, 3, 5), knock down of specifically SIRT1 resulted in enhanced acetylation of NICD. Moreover, wild type SIRT1, but not a catalytically inactive mutant catalyzed the deacetylation of NICD in a nicotinamid-dependent manner. SIRT1, but SIRT2, SIRT3 or SIRT5, associated with NICD through its catalytic domain demonstrating that SIRT1 is a direct NICD deacetylase. Enhancing NICD acetylation by either overexpression of p300 or inhibition of SIRT1 activity using NAM or RNAi-mediated knock down resulted in enhanced NICD protein stability by blocking its ubiquitin-mediated degradation. Consistent with these results, loss of SIRT1 amplified Notch target gene expression in endothelial cells in response to NICD overexpression or treatment with the Notch ligand Dll4. In summary, our results identify reversible acetylation of NICD as a novel molecular mechanism to control Notch signaling and suggest that deacetylation of NICD by SIRT1 plays a key role in the dynamic regulation of Notch signaling in endothelial cells.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

Notch Signaling Pathway: Find New Channel during Liver Repair and Regeneration

2021 ◽  
Vol 28 ◽  
Author(s):  
Amir Valizadeh ◽  
Ali Sayadmanesh ◽  
Zatollah Asemi ◽  
Forough Alemi ◽  
Ata Mahmoodpoor ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
The Body ◽  
Liver Disorders ◽  
Liver Repair ◽  
Underlying Mechanisms

: The liver is one of the significant regenerative organs in the body. Nevertheless, underlying molecular mechanisms regulating liver repair and regeneration following resection or damage remain largely unknown. The Notch signaling pathway is a profoundly evolutionarily well‐conserved cell signaling system that plays mostly in multicellular organisms' development. Malfunctions in this pathway lead to the progression of several liver disorders, including hepatoblastoma (HB), cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), and so on. Notch pathway plays a fundamental role in cell fate during the embryonic stage's progression to the adult stage in liver tissue. Modulation of Notch signaling may be used in the vast array of patients who succumb to cirrhosis owing to chronic hepatitis by virus infection. This review describes the underlying mechanisms of the Notch signaling pathway in liver development and regeneration briefly and discusses how this pathway leads to better liver disorders in the clinic.

scholarly journals EXPRESIÓN DE LOS GENES Serrate1 Y Notch1 DURANTE EL DESARROLLO DEL TERCIO MEDIO FACIAL DEL EMBRIÓN DE POLLO

2015 ◽  
Vol 21 (1) ◽  
Author(s):  
Daniel Mauricio Meza Lasso ◽  
Cindy Johana Peña Barrera ◽  
Francy Yomara Bayona Rodriguez ◽  
Belfran Alcides Carbonell Medina ◽  
Clementina Infante
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Expression Patterns ◽  
Notch Pathway ◽  
Cell Communication ◽  
Gallus Gallus ◽  
Notch Signaling Pathway ◽  
Cellular Processes

<p class="p1"><strong>RESUMEN</strong></p><p class="p2">La vía de señalización Notch se caracteriza por mediar la comunicación célula-célula, regulando diferentes procesos celulares como proliferación, apoptosis y definición del destino celular. Esta vía ha sido implicada en el desarrollo de estructuras craneofaciales como paladar, diente y bóveda craneal. El objetivo de esta investigación fue identificar los patrones de expresión de los genes componentes de la vía Notch, Serrate1 y Notch1, durante el desarrollo del tercio medio facial. Se utilizaron embriones de pollo (Gallus gallus) seleccionados de acuerdo a los criterios de Hamilton y Hamburger y sobre los cuales se realizó hibridación in situ con ribosondas marcadas con Digoxigenina (DIG), para luego ser detectadas con anticuerpos Anti-Dig. Los resultados mostraron expresión de los genes evaluados, en las prominencias maxilares (pmx) y frontonasal (pfn) durante el desarrollo del tercio medio facial. Estos resultados sugieren una probable participación de la vía Notch a través de estos genes, en los diferentes procesos celulares que determinan la morfogénesis y el desarrollo del tercio medio facial.</p><p class="p2"><strong>ABSTRACT</strong></p><p class="p2">The Notch signaling pathway is characterized by mediate cell-cell communication, regulating different cellular processes as proliferation, apoptosis and cell fate definition. This pathway has been implicated in craniofacial structures development as palate, teeth and cranial vault. The objective of this research was to identify the genes expression patterns of some Notch signaling pathway components, Serrate1 and Notch1, during the midface development. It was used chicken embryos (Gallus gallus) selected according to Hamilton and Hamburger criteria. We performed in situ hybridization with Digoxigenin (DIG)-labeled riboprobes and detected with the antibody Anti-Dig. The results showed the expression of the evaluated genes in the maxillary (pmx) and frontonasal (pfn) prominences during the midface development. These results suggest a probable involvement of the Notch pathway through these genes in different cellular processes that determine midface morphogenesis and development.</p><p class="p2"> </p>

scholarly journals Adding a “Notch” to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach

2021 ◽  
Vol 9 ◽  
Author(s):  
Luisa Marracino ◽  
Francesca Fortini ◽  
Esmaa Bouhamida ◽  
Francesca Camponogara ◽  
Paolo Severi ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Molecular Mechanisms ◽  
Notch Pathway ◽  
Biological Processes ◽  
Rna Sequences ◽  
Regulate Gene Expression ◽  
Cellular Processes ◽  
Non Coding Rna ◽  
Mirnas Expression

Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.

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

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Maria R Stupnikov ◽  
Ying Yang ◽  
Munemasa Mori ◽  
Jining Lu ◽  
Wellington V Cardoso
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Notch Pathway ◽  
Airway Epithelial ◽  
Multiple Organs ◽  
Distinct Cell ◽  
Club Cells ◽  
Core Components ◽  
Conducting Airways

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.

scholarly journals Increasing Notch signaling antagonizes PRC2-mediated silencing to promote reprograming of germ cells into neurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Stefanie Seelk ◽  
Irene Adrian-Kalchhauser ◽  
Balázs Hargitai ◽  
Martina Hajduskova ◽  
Silvia Gutnik ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Germ Cells ◽  
Molecular Mechanisms ◽  
Notch Signaling Pathway ◽  
Germline Stem Cells ◽  
Polycomb Repressive Complex 2 ◽  
C Elegans ◽  
Functional Studies

Cell-fate reprograming is at the heart of development, yet very little is known about the molecular mechanisms promoting or inhibiting reprograming in intact organisms. In the C. elegans germline, reprograming germ cells into somatic cells requires chromatin perturbation. Here, we describe that such reprograming is facilitated by GLP-1/Notch signaling pathway. This is surprising, since this pathway is best known for maintaining undifferentiated germline stem cells/progenitors. Through a combination of genetics, tissue-specific transcriptome analysis, and functional studies of candidate genes, we uncovered a possible explanation for this unexpected role of GLP-1/Notch. We propose that GLP-1/Notch promotes reprograming by activating specific genes, silenced by the Polycomb repressive complex 2 (PRC2), and identify the conserved histone demethylase UTX-1 as a crucial GLP-1/Notch target facilitating reprograming. These findings have wide implications, ranging from development to diseases associated with abnormal Notch signaling.

Notch signaling in the developing cardiovascular system

2007 ◽  
Vol 293 (1) ◽  
pp. C1-C11 ◽  
Author(s):  
Kyle Niessen ◽  
Aly Karsan
Keyword(s):  
Notch Signaling ◽  
Cardiovascular System ◽  
Cell Fate ◽  
Heart Valves ◽  
Critical Role ◽  
Notch Pathway ◽  
Alagille Syndrome ◽  
Congenital Defects ◽  
Mesenchymal Transition

The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate. Recent findings have demonstrated a critical role of Notch in the developing cardiovascular system. Notch signaling has been implicated in the endothelial-to-mesenchymal transition during development of the heart valves, in arterial-venous differentiation, and in remodeling of the primitive vascular plexus. Mutations of Notch pathway components in humans are associated with congenital defects of the cardiovascular system such as Alagille syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and bicuspid aortic valves. This article focuses on the role of the Notch pathway in the developing cardiovascular system and congenital human cardiovascular diseases.

scholarly journals The Protein Phosphatase 4 complex promotes the Notch pathway and wingless transcription

2017 ◽  
Author(s):  
Eric T. Hall ◽  
Tirthadipa Pradhan-Sundd ◽  
Faaria Samnani ◽  
Esther M. Verheyen
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Protein Phosphatase ◽  
Genetic Interaction ◽  
Notch Pathway ◽  
Regulatory Subunits ◽  
Cellular Processes ◽  
Summary Statement ◽  
Notch Pathways

AbstractThe Wnt/Wingless (Wg) pathway controls cell fate specification, tissue differentiation and organ development across organisms. Using an in vivo RNAi screen to identify novel kinase and phosphatase regulators of the Wg pathway, we identified subunits of the serine threonine phosphatase Protein phosphatase 4 (PP4). Knockdown of the catalytic and the regulatory subunits of PP4 cause reductions in the Wg pathway targets Senseless and Distal-less. We find that PP4 regulates the Wg pathway by controlling Notch-driven wg transcription. Genetic interaction experiments identified that PP4 likely promotes Notch signaling within the nucleus of the Notch-receiving cell. Although the PP4 complex is implicated in various cellular processes, its role in the regulation of Wg and Notch pathways was previously uncharacterized. Our study identifies a novel role of PP4 in regulating Notch pathway, resulting in aberrations in Notch-mediated transcriptional regulation of the Wingless ligand. Furthermore, we show that PP4 regulates proliferation independent of its interaction with Notch.Summary statementThe protein phosphatase 4 complex promotes Notch signaling and target gene expression during Drosophila wing development.

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