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

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

PROVIDER: PRJNA798353 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17653378_1.fastq.gz	Fastqsanger.gz
	SRR17653378_2.fastq.gz	Fastqsanger.gz
	SRR17653379_1.fastq.gz	Fastqsanger.gz
	SRR17653379_2.fastq.gz	Fastqsanger.gz
	SRR17653380_1.fastq.gz	Fastqsanger.gz

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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: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 "reactivated" 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 postnatal β cells impaired glucose-stimulated insulin secretion 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 pseudoislet formation. Consistent with our mouse data, Notch and Ephrin signaling were increased in metabolically inflexible β cells in patients with T2D. These studies suggest that β cell Notch/Ephrin signaling can permanently alter islet architecture during a morphogenetic window in early life.

| S-EPMC8986078 | biostudies-literature

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

Project description: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.

2018-08-13 | PXD005333 | Pride

Eph-ephrin signaling couples endothelial cell sorting and arterial specification

Project description:Cell segregation allows the compartmentalization of cells with similar fates during morphogenesis, which can be enhanced by cell fate plasticity in response to local molecular and biomechanical cues. Endothelial tip cells in the growing retina, which lead vessel sprouts, give rise to arterial endothelial cells and thereby mediate arterial growth. Here, we have combined cell type-specific and inducible mouse genetics, flow experiments in vitro, single cell RNA sequencing and biochemistry to show that the balance between ephrin-B2 and its receptor EphB4 is critical for arterial specification, cell sorting and arteriovenous patterning. At the molecular level, elevated ephrin-B2 function after loss of EphB4 enhances signaling responses by the Notch pathway, VEGF and the transcription factor Dach1, which is influenced by endothelial shear stress. Our findings reveal how Eph-ephrin interactions integrate cell segregation and arteriovenous specification in the vasculature, which has potential relevance for human vascular malformations caused by EPHB4 mutations.

2024-01-30 | GSE223738 | GEO

Identification of immediate early transcriptional targets of ephrin-B1 forward signaling

Project description:The goal of this study was to identify immediate early transcriptional targets of ephrin-B1 forward signaling that are relevant to palatogenesis. The Ephs compose a family of receptor tyrosine kinase signaling molecules that can be activated by their cognate ligands, the ephrins. Despite the importance of Eph/ephrin signaling in a wide variety of developmental and cell biological processes, a potential downstream transcriptional response has not been explored. To understand the role of ephrin-B1 signaling in palatogenesis, we examined transcriptional response to ephrin-B1 in a primary mouse embryonic palatal shelf cell culture system. We find an immediate early signature of gene expression that reflects the activation of Erk/MAPK signaling by ephrin-B1 signaling in the palatal shelves. Induction of primary palate cells with 2 ug/ml of pre-clustered ephrin-B1 for one hour. Uninduced primary palate cells are the control. Four replicates each.

2010-09-20 | E-GEOD-23539 | biostudies-arrayexpress

Identification of immediate early transcriptional targets of ephrin-B1 forward signaling

2010-09-21 | GSE23539 | GEO

Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

Project description:Down Syndrome Induced Senescence Disrupts the Nuclear Architecture of Neural Progenitors

| PRJNA769437 | ENA

Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

Project description:Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function

| PRJNA1000777 | ENA

Notch

Project description:Notch

| PRJNA988118 | ENA

Effect of Ephrin-A5 DNA Nanocalipers stimulation of EphA2 receptor signaling in U3013 cell line

Project description:Ligand binding induces extensive spatial reorganization and clustering of the EphA2 receptor at the cell membrane. It has previously been shown that the nanoscale spatial distribution of ligands modulates EphA2 receptor reorganization, activation and the invasive properties of cancer cells. However, the mechanisms by which cells transduce ligand nanoscale spatial distribution signals have not been elucidated. Here we used DNA origami nanocalipers to control the positions of ephrin-A5 ligands at the nanoscale and investigated the transcriptional responses following ligand binding. Using mRNA sequencing, we determined the transcriptional profiles of glioblastoma cells treated with nanocalipers presenting a single ephrin-A5 dimer or two dimers spaced 14, 40 or 100 nm apart. We observed divergent transcriptional responses to ephrin-A5 nano-organization, with ephrin-A5 dimers spaced 40 or 100 nm apart showing the highest levels of differential expressed genes compared to treatment with n anocalipers that do not present ephrin-A5. These findings show that the nanoscale organization of ephrin-A5 modulates transcriptional responses to EphA2 activation.

2020-04-07 | GSE138622 | GEO

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