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Series GSE249170 Query DataSets for GSE249170
Status Public on Feb 23, 2024
Title β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Objective
Notch signaling is re-activated in β cells from obese mice, and is causal to β cell dysfunction. Notch activity is determined in part by expression of transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant β cell dysfunction in obese mice.
Methods
We assessed expression of Notch pathway components in diet-induced obese (DIO) or leptin receptor-deficient (db/db) mice, and performed single cell RNA sequencing (scRNAseq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, β cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets.
Results
Jag1 was the only Notch ligand that tracked with increased Notch activity in DIO and db/db mice. Consistently, JAG1 tracked with Notch activity in metabolically inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from DIO and db/db mice potentiated GSIS ex vivo. To demonstrate if β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic mice (β-Jag1TG), which showed impaired glucose intolerance due to reduced GSIS. However, β cell-specific Jagged1 loss-of-function (β-Jag1KO) did not protect against HFD-induced insulin secretory defects or glucose intolerance.
Conclusions
Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that β cells are not a likely source of the Jagged1 signal.
 
Overall design RNA-seq of pancreatic islets from β cell Jag1-gain of function model
 
Contributor(s) Suda N, Pajvani U
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Submission date Dec 01, 2023
Last update date Feb 23, 2024
Contact name Utpal Pajvani
E-mail(s) up2104@cumc.columbia.edu
Organization name Columbia University Medical Center
Street address 1150 St. Nicholas Avenue
City New York
State/province NY
ZIP/Postal code 10032
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (6)
GSM7927731 Control-1 [LN002]
GSM7927732 Control-2 [LN003]
GSM7927733 Control-3 [LN004]
Relations
BioProject PRJNA1047593

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE249170_TetO-Jag1-Raw_count_table.txt.gz 298.3 Kb (ftp)(http) TXT
GSE249170_tetO-Jag1-DEGs.txt.gz 477.0 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA

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