Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Notch2 Expressed by Myofibers Influences Muscle Mass and Fiber Types

ABSTRACT: Notch receptors play crucial roles in the cell-fate decisions of tissue stem cells during development and regeneration. Notch1-3 receptors are expressed by satellite cells and their progeny. Here we found that Notch2, but not Notch1 or Notch3, was expressed in fully differentiated myofibers. Using transgenic mice that expressed a muscle-specific active form of Notch2 (N2ICD-mTG), we found that Notch2 activation remarkably reduced muscle mass and strength with a shift toward slow fibers. Transcriptome analyses revealed that growth differentiation factor 11 (GDF11) was highly up-regulated in muscles of N2ICD-mTG mice, and crucially, N2ICD-induced muscle atrophy was rescued by siRNA-mediated reduction of GDF11 expression. These data suggest that Notch2 functions in muscle to regulate muscle mass, in part, through induction of GDF11 expression, and reveal a novel aspect of Notch signaling in a terminally differentiated adult tissue.

ORGANISM(S): Mus musculus

PROVIDER: GSE83929 | GEO | 2020/01/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Notch1 and Notch2 signaling from distinct cellular sources exclusively but cooperatively regulate fetal myogenesis

Project description:During developmental myogenesis, some continuously proliferating myogenic progenitors (MPs) sustain stem/progenitor states while the rest differentiate into myocytes to form myofibers by fusion. To generate sufficient muscle, fine regulations of cell fate decision of MPs are crucial. Notch signaling has been known to regulate embryonic MPs (eMPs) that play a role in primary myogenesis by promoting cell cycle exit and suppressing premature differentiation. However, the role of Notch signaling in fetal MPs (fMPs) during secondary myogenesis is elusive because the development of fMPs already has been abrogated in Notch manipulation models. In this study, we investigated the role of Notch signaling in fMPs at an individual Notch receptor level. Surprisingly we found that Notch1 and Notch2, most similar among four Notch receptors, distinctly regulate fMPs: Notch1 induces cell cycle exit and Notch2 suppresses premature differentiation, presumably by canonical Notch signaling pathway. Additionally, we suggest that Notch1 and Notch2 signals are regulated by the ligands on myofibers and MP-lineage cells, respectively. This study will lay the groundwork for the in-depth understanding of Notch signaling in muscle formation from embryonic myogenesis to adult muscle regeneration.

2022-12-31 | GSE190521 | GEO

Notch2 deficiency prevents muscle atrophy induced by mechanical unloading and diabetes.

Project description:Notch signaling plays essential roles in maintenance of muscle stem cell pool. We found that Notch2, but not Notch1 and Notch3, is expressed in fully differentiated myofibers. To study the specific role of Notch2 in adult myofibers, we generated muscle-specific Notch2-knockout mice. Here, we showed that muscle-specific Notch2 deficiency prevented muscle atrophy induced by hindlimb unloading and diabetes millitus. RNA sequencing analysis revealed that the loss of Notch2 gene in myofibers inhibited gene responses to unloading and diabetes. Especially, several FoxO-target genes and atrogenes were upregulated in wildtype muscles but not in Notch2-deficient muscles by unloading and diabetes. Thus, our characterization of muscle-specific Notch2-knockout mice indicates that Notch2 acts as a regulatory factor of skeletal muscle plasticity and could be a therapeutic target of muscle atrophy.

2022-01-07 | GSE161693 | GEO

Discovery of biomarkers predictive of GSI response in triple negative breast cancer and adenoid cystic carcinoma

Project description:Next generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple negative breast cancers (TNBC, 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with pacitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in TNBC patients. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD low tumors without NOTCH1 mutations were resistant. Gene expression profiling for Notch-sensitive cancer cell lines using RNA-seq, each sample with triplicates

2014-08-14 | E-GEOD-59810 | biostudies-arrayexpress

Discovery of biomarkers predictive of GSI response in triple negative breast cancer and adenoid cystic carcinoma

2014-08-14 | GSE59810 | GEO

Plasma membrane-derived extracellular microvesicles mediate non-canonical intercellular NOTCH signaling

Project description:ARMMs (arrestin domain-containing protein 1 [ARRDC1]-mediated microvesicles) are extracellular vesicles that bud directly atthe plasma membrane. However, little is known about the physiological function of these vesicles. Here we report that secreted ARMMs contain active NOTCH receptors and mediate a non-canonical intercellular NOTCH signaling. Masss pectrometry of purified ARMMs identifiedNOTCH2 as a protein component of the vesicles. The NOTCH protein in ARMMs contains the critical intracellular region (NICD) that is required for its transcriptional activity in the nucleus. ARRDC1 overexpression increased the NOTCH2 incorporation into ARMMs. Conversely, CRISPR-mediated knockout of ARRDC1 dramatically reduced the amount of NOTCH2 in secreted ARMMs. The incorporation of NOTCH2 into ARMMs is facilitated by the ITCH E3 ligase and ADAM10, which are also secreted into ARMMs. We showed NOTCH2 in ARMMs delivered into recipient cells is further activated by γ-secretase cleavage to induce NOTCH-specific signaling in recipient cells. Together, our findings revealed a role for ARMMs in a novelNOTCH signaling pathway that acts in distance beyond direct cell-cell contact.

2017-10-11 | PXD006416 | Pride

Neuronal_Notch_Exosome_YZWang_2023_Cell_Reports

Project description:Summary Extracellular vesicles (EVs) facilitate intercellular communication by transferring cargo between cells in a variety of tissues. However, how EVs achieve cell type-specific intercellular communication is still largely unknown. We found that Notch1 and Notch2 proteins are expressed on the surface of neuronal EVs that have been generated in response to neuronal excitatory synaptic activity. Notch ligands bind these EVs on the neuronal plasma membrane, trigger their internalization, activate the Notch signaling pathway, and drive the expression of Notch target genes. The generation of these neuronal EVs requires the ESCRT-associated protein Alix. Adult Alix conditional knockout mice have reduced hippocampal Notch signaling activation and glutamatergic synaptic protein expression. Thus, EVs facilitate neuron to neuron communication via the Notch receptor-ligand system in the brain.

2023-12-06 | MSV000093592 | MassIVE

Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embyronic and induced pluripotent cells

Project description:Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells (hPSCs) of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and siRNA to Notch receptors we have demonstrated that Notch1, but not Notch2 activation, induced HES1 expression and generation of committed hematopoietic progenitors. Using gain and loss of function approaches, this was shown to be attributed to Notch signaling regulation through HES1, that dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs. endothelial fate specification.

2013-06-01 | GSE47466 | GEO

Effect of depletion of Notch signaling genes in C2C12 cells on the activation of Notch pathway activity in response to stimulation by plated ligand

Project description:To obtain a Notch-depleted base cell line into which we could integrate specific ligands or receptors for quantitative analysis of Notch signaling interactions, we conducted 2 rounds of transfection with RNPs (ribonucleoproteins) consisting of gRNAs targeting Notch2 and Jagged1 complexed with Cas9 protein. After antibiotic selection and screening of monoclonal colonies, we obtained the C2C12-Nkd clone, which showed loss of Notch2 protein and Jag1 transcript.

2023-06-02 | GSE233573 | GEO

Conditional ablation of the Notch2 receptor in the ocular lens

Project description:Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors has not been previously investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, and cataracts. Notch2 mutants also had a persistent lens stalk phenotype at E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2) and Trp63 (p63) that negatively regulates Wnt signaling. Although removal of Notch2 phenocopied the increased proportion of fiber cells of Rbpj and Jag1 conditional mutant lenses, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. Instead, we found that the Notch2 normally blocks progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.

2011-12-31 | GSE31643 | GEO

Conditional ablation of the Notch2 receptor in the ocular lens

2011-12-31 | E-GEOD-31643 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data