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Delta-like ligand 4-Notch signaling inhibition regulates pancreatic islet function and insulin secretion

ABSTRACT: Dll4-Notch signaling is required for cell fate decisions and neoplasias. However, emerging evidence suggests a role for Dll4-Notch signaling in metabolic and immune diseases. To date, there is no evidence of a direct effect of Dll4-Notch signaling inhibition on pancreatic islet function and insulin secretion.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Antigoni Manousopoulou

LAB HEAD: Spiros D. Garbis

PROVIDER: PXD005333 | Pride | 2018-08-13

REPOSITORIES: Pride

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			Action	DRS
	17OCT16_Sevi_pancreas.pep.pep.xml	Pepxml
	17OCT16_Sevi_pancreas.prot.prot.xml	Xml
	17OCT16_Sevi_pancreas_13.raw	Raw
	17OCT16_Sevi_pancreas_13b.raw	Raw
	17OCT16_Sevi_pancreas_14.raw	Raw

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Publications

Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion.

Billiard Fabienne F Karaliota Sevasti S Wang Bei B Stellas Dimitrios D Serafimidis Ioannis I Manousopoulou Antigoni A Koutmani Yiassemi Y Ninou Elpiniki E Golubov Jacquelynn J DaNave Amanda A Tsakanikas Panagiotis P Xin Yurong Y Zhang Wen W Sleeman Matthew M Yancopoulos George D GD Murphy Andrew J AJ Garbis Spiros D SD Karalis Katia K Skokos Dimitris D

Cell reports 20180128 4

Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pat ...[more]

PMID: 29386132

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Notch-mediated Ephrin signaling disrupts islet architecture and β cell function

Project description:Altered islet architecture is associated with β cell dysfunction and Type 2 Diabetes (T2D) progression, but molecular effectors of islet spatial organization remain mostly unknown. Although Notch signaling is known to regulate pancreatic development, we observed “re-activated” β cell Notch activity in obese mouse models. To test the repercussions and reversibility of Notch effects, we generated doxycycline-dependent, β cell-specific Notch gain-of-function mice. As predicted, we found that Notch activation in post-natal β cells impaired glucose stimulated insulin secretion (GSIS) and glucose intolerance, but we observed a surprising remnant glucose intolerance after doxycycline withdrawal and cessation of Notch activity, associated with a marked disruption of normal islet architecture. Transcriptomic screening of Notch-active islets revealed increased Ephrin signaling. Commensurately, exposure to Ephrin ligands increased β cell repulsion, and impaired murine and human pseudo-islet formation. Consistent with our mouse data, Notch and Ephrin signaling are increased in metabolically-inflexible β cells in patients with T2D. These studies suggest than islet architecture can be permanently altered by β cell Notch/Ephrin signaling during a morphogenetic window in early life.

2022-02-21 | GSE193888 | GEO

Notch-mediated Ephrin signaling disrupts islet architecture and β cell function

Project description:Notch-mediated Ephrin signaling disrupts islet architecture and β cell function

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Hematopoietic stem cells treated with the Notch ligand Delta 4 HSC_notch_IGR

Project description:The Notch pathway regulates cell-fate decisions in a wide variety of cell types, often inhibiting particular differentiation programs and permitting either self-renewal or differentiation along alternate pathways. Notch receptors and Notch ligands have been found on hematopoietic stem cells (HSC) or marrow stromal cells. In the present study, through a microarray approach, we analyzed the gene expression variations from cultured murine HSC with or without a Notch ligand Delta4 at 6 hours, 12 hours and 24 hours after the induction of the Notch pathway. Keywords: time course

2006-06-29 | GSE5135 | GEO

Hematopoietic stem cells treated with the Notch ligand Delta 4 HSC_notch_IGR

2010-07-01 | E-GEOD-5135 | biostudies-arrayexpress

A Notch ligand, Delta-like 1 functions as an adhesion molecule for mast cells

Project description:To assess the effect of over-expression of Delta-like 1 on OP9 cells on gene expression in terms of Notch signaling and adhesion molecules, gene expressions of OP9, OP9-GFP (carrying GFP gene) and OP9-DL1 (carrying GFP and DL1 gene) cells (Immunity 2002;17:749-756) were analyzed. Gene expression of OP9, OP9-GFP and OP9-DL1 were compared.

2010-10-01 | E-GEOD-22659 | biostudies-arrayexpress

A Notch ligand, Delta-like 1 functions as an adhesion molecule for mast cells

2010-10-01 | GSE22659 | GEO

Genome-wide effect of islet isolation and in vitro culture on gene expression profile of pancreatic beta-cells enriched tissue.

Project description:It is known that the stresses encountered during islet isolation have deleterious effects on beta-cell physiology. The nature of these effects, however, is incompletely known, partly due to the heterogeneity of islet preparations. The objective was to assess the genome-wide effect of islet isolation and in-vitro culture on beta-cell transcriptome. Beta cells identified by their intrinsic autofluorescence, were captured from donor pancreas and isolated islets using Laser Capture Microdissection. Beta cells from donor pancreas serve as the control. Our results indicated induction of a strong inflammatory response induced by islet isolation which continues during in vitro culture manifested by upregulation of several cytokines, chemokines and their receptors. IL-8 was induced by 3.6-fold and 56-fold in fresh and 3-days cultured islets respectively. Concordantly, several pancreatic progenitor cell-specific transcription factors like were upregulated in cultured islets, suggesting progressive transformation of mature beta-cell phenotype toward an immature endocrine cell phenotype. There are three sample types in our experiment; 1) beta-cells captured from the frozen sections of donor pancreas n=8, 2) beta cells extracted from islets frozen immediately after isolation (d0 islets) n=8 and, 3) beta cells extracted from isolated islets frozen after culturing for 3 days (d3 islets) n=5. For the analysis, beta cells from pancreas were considered as the reference point.

2012-02-12 | E-GEOD-29113 | biostudies-arrayexpress

The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration

Project description:Hair cells (HCs) within the inner ear cochlea are highly specialized mechano-sensory cells that enable us to detect sound. In humans and other mammals, HC loss is permanent and a leading cause of deafness. Recent studies in newborn mice revealed that supporting cells (SCs) have the capacity to form cochlear HCs, and that inhibition of Notch signaling dramatically increases the otherwise low rate of SC-to-HC conversion. It has been proposed that in the absence of HCs, the SC-specific Notch ligand Jagged1 (JAG1) mediates the HC-repressive role of Notch signaling. Here we show that conditional deletion of Jag1 at postnatal day2 (P2) increases the rate of HC formation/regeneration in cochlear tissue and organoids. However, Jag1 deficiency also reduces the expression of key progenitor and metabolic genes and attenuates PI3K-Akt-mTOR signaling in cochlear SCs and Kölliker’s cells and we show that Notch1 and Notch2 are critical for mediating these pro-growth functions of Jag1. Conversely, we show that increasing JAG1/Notch signaling enhances the mitotic capacity of cochlear SCs/ Kölliker’s cells. Finally, we show that JAG1 expression declines in SCs as they undergo maturation, and that stimulation of JAG1 signaling boosts the ability of maturing cochlear SCs to form HCs in an mTOR-dependent manner.

2025-06-21 | GSE266157 | GEO

Sequential ligand-dependent Notch signaling activation regulates valve primordium formation and morphogenesis

Project description:Our studies identify a mechanism of signaling crosstalk during valve morphogenesis that sheds light on the origin of congenital heart defects associated with reduced Notch function.

2018-01-31 | GSE74556 | GEO

Notch Signaling Enhances Bone Regeneration in the Zebrafish Mandible

Project description:Loss or damage to the mandible due to trauma, treatment of oral malignancies, and other diseases is currently treated using bone grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to their mandibular bone, and thus offer an opportunity to understand how to boost intrinsic healing ability. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes. We also show that modulation of Notch signaling during the initial postoperative period results in lasting changes to regenerate bone quantity one month later. Notch signaling is required for mandibular bone healing, as pharmacological inhibition of Notch signaling blocks cartilage callus formation and results in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates regenerative ossification. Mechanistically, we report that postoperative Notch signaling regulates multiple phases of chondroid regeneration and patterns callus metabolic landscape. Given conserved functions of Notch signaling in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing may have therapeutic value.

2022-03-07 | PXD027280 | Pride

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