β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.
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ABSTRACT:
PROVIDER: PRJNA1047593 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27018959_1.fastq.gz | Fastqsanger.gz | |||
| SRR27018959_2.fastq.gz | Fastqsanger.gz | |||
| SRR27018960_1.fastq.gz | Fastqsanger.gz | |||
| SRR27018960_2.fastq.gz | Fastqsanger.gz | |||
| SRR27018961_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2024-02-23 | GSE249170 | GEO
Project description:ObjectiveNotch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin secretory defects in obese mice.MethodsWe assessed expression of Notch pathway components in high-fat diet-fed (HFD) or leptin receptor-deficient (db/db) mice, and performed single-cell RNA sequencing (scRNA-Seq) 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.ResultsJag1 was the only Notch ligand that tracked with increased Notch activity in HFD-fed and db/db mice, as well as in metabolically-inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from HFD-fed 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 (β-Jag1TG) and loss-of-function (iβ-Jag1KO) mice. While forced Jagged1 impaired glucose intolerance due to reduced GSIS, loss of β cell Jagged1 did not protect against HFD-induced insulin secretory defects.ConclusionsJagged1 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.
| S-EPMC10877406 | biostudies-literature
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during ?-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature ?-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn ?-cells, suggesting that they contribute to the limited proliferative capacity of adult ?-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=5) or 3-month-old male rat (n=6) were taken. Total RNA was extracted and microRNA profiling was performed using the Illumina TruSeq small RNA kit and single-end sequencing.
2014-09-06 | E-GEOD-61180 | biostudies-arrayexpress
Project description:Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. Goals: Creb3L1 is the closest related human orthologue of Drosophila CrebA. CrebA is required to upregulate genes encoding the protein machinery and cargo in specialized secretory cells. To determine if the human orthologues of CrebA, Creb3L1 and Creb3L2, perform the same function, we expressed the truncated active form of Creb3L1 in non-secretory HeLa cells. We then performed microarray experiments and found that active Creb3L1 is sufficient to upregulate genes encoding the protein machinery of the secretory pathway, as observed with Drosophila CrebA. HeLa cells were transiently co-transfected with truncated Creb3L1 (Creb3L1 T) and GFP. Following 20 hours in culture, GFP positive cells were isolated by FACS and RNA was extracted using the Rneasy kit (Qiagen). As a control, mock transfected cells were also subjected to cell sorting and RNA was extracted using the same protocols. At least three replicates were obtained for each group.
2010-10-18 | E-GEOD-23334 | biostudies-arrayexpress
Project description:Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. This SuperSeries is composed of the following subset Series: GSE23334: Active Creb3L1 can upregulate secretory pathway genes in HeLa cells GSE23346: CrebA is a major and direct regulator of secretory pathway gene expression Refer to individual Series
2010-10-18 | E-GEOD-23349 | biostudies-arrayexpress
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=3) or 3-month-old male rat (n=3) were taken. Total RNA was extracted and mRNA profiling via Illumina single-end sequencing of mRNA-seq libraries was performed.
2014-09-06 | E-GEOD-61179 | biostudies-arrayexpress
Project description:miRNA expression profiles of HMECs treated with 40mM Jagged1 (JAG1) or the control peptide for 1 day Genome-wide miRNA PCR array analysis was performed using human miRNA PCR arrays (MIHS216Z, SABiosceinces) acccording to the manufacturer's instructions
2014-05-30 | E-GEOD-56801 | biostudies-arrayexpress
Project description:miRNA expression profiles of HMECs treated with 40mM Jagged1 (JAG1) or the control peptide for 1 day
2014-05-30 | GSE56801 | GEO
Project description:Transcriptional profiling of MC3T3-E1 osteoblasts that were flow cytometry-separated from cocultures with control or Jagged1-overexpressing tumor cells and treated with either DMSO control or 1μM MRK-003 (gamma-secretase inhibitor). One cell line (MC3T3-E1) cells: four different experimental conditions: cultured with (1) control tumor cells + DMSO; (2) Jagged1-overexpressing tumor cells + DMSO; (3) control tumor cells + MRK-003; (4) Jagged1-overexpressing tumor cells + MRK-003. Each experiment has two biological replicates. Total, 8 samples.
2010-08-15 | E-GEOD-20517 | biostudies-arrayexpress
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation.
2014-09-06 | GSE61179 | GEO