Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA485745 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7695630.fastq.gz | Fastqsanger.gz | |||
| SRR7695640_1.fastq.gz | Fastqsanger.gz | |||
| SRR7695640_2.fastq.gz | Fastqsanger.gz | |||
| SRR7695631.fastq.gz | Fastqsanger.gz | |||
| SRR7695641.fastq.gz | Fastqsanger.gz |
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Project description:RNAseq data indicate that in the human brain, most neurons co-express the brain-derived neurotrophic factor (BDNF) receptor TrkB and the Neurotrophin-3 (NT3) receptor TrkC. Because NT3 can also activate TrkB and TrkB is expressed at higher levels compared with TrkC, it has been difficult thus far to explore TrkC-mediated signaling. To this end, neurons were generated from human embryonic stem cells lacking the BDNF receptor TrkB using CRISPR/Cas9. These neurons were found to respond to very low concentrations of NT3, lower than the concentrations of BDNF needed to activate TrkB. In order to compare the transcriptional changes following treatment with NT3 RNA-seq analysis was performed and the results compared with those previously obtained following treatment of wild-type neurons with BDNF Merkouris et al. PMID: 29987039. The results indicate that downstream of TrkC activation, most of the changes in gene expression are similar to those seen after TrkB activation. The results also show that exposure to sub-saturating concentrations of either BDNF or NT3 does not cause receptor downregulation as seen with saturating ligand concentrations and that the receptors can be re-activated.
2022-03-22 | E-MTAB-11566 | biostudies-arrayexpress
Project description:The nervous system plays an increasingly appreciated role in the regulation of cancer. In gliomas, neuronal activity drives tumor progression through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumor proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signaling through the receptor TrkB (tropomyosin receptor kinase B), BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity that contributes to memory and learning in the healthy brain. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells robustly inhibits tumor progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.
2023-03-01 | GSE222481 | GEO
Project description:The nervous system plays an increasingly appreciated role in the regulation of cancer. In gliomas, neuronal activity drives tumor progression through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumor proliferation. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity and strength. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signaling through the receptor TrkB (tropomyosin receptor kinase B), BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity that contributes to memory and learning in the healthy brain. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells robustly inhibits tumor progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.
2023-09-19 | GSE222560 | GEO
Project description:In Alzheimer’s disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, as well as synaptic transmission and plasticity. In addition to compromising canonical BDNF signalling pathways, TrkB-FL cleavage produces an intracellular fragment (TrkB-ICD), which was shown to accumulate in the nucleus and to display tyrosine kinase activity. To dissect the role of TrkB-ICD overexpression from the loss of endogenous signaling throught TrkB-FL, we used lentiviruses to overexpress the TrkB-ICD sequence in cultured primary cortical neurons and performed morphological, electrophysiological and transcriptomics studies. While TrkB-ICD overexpression did not affect cell survival, it caused a significant decrease in the number of dendritic spines, both compared to untransduced and GFP-transduced neurons. Furthermore, TrkB-ICD overexpressing neurons presented a hyperpolarized resting membrane potential and increased frequency of miniature excitatory postsynaptic currents (mEPSCs). Finally, TrkB-ICD overexpression was associated with the upregulation of genes involved in (i) neuronal survival, growth and differentiation; (ii) neuronal cytoarchitecture and spine morphology; (iii) neurodegenerative processes, including AD; and (iv) synaptic transmission and plasticity. Overall, these results show that TrkB-ICD overexpression causes dendritic spine loss, alters excitatory synaptic transmission and causes transcriptome-wide changes, namely in genes coding for proteins involved in synaptic processes.
2024-07-30 | GSE271487 | GEO
Project description:As a result of a large number of in vitro as well as in vivo experiments with rodents, brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB are now widely appreciated to play major roles in brain function. There is also a growing appreciation that decreased BDNF signalling may be a significant component in a wide range of brain dysfunction in humans based on the discovery of mutations and polymorphisms in the corresponding genes. Human neurons generated in vitro had been shown to be responsive to TrkB phosphorylation upon treatment with BNDF, TrkB agonist ZEB85, the related factor neurotrophin-4 (NT4). In order to compare the transcriptional changes upon treatment with the three TrkB ligands RNA-seq analysis was deployed. Cultures had been treated in triplicates with BDNF, ZEB85 or NT4 for 30 minutes, 2 hours, 12 hours and 24 hours, while non treated controls were lysed at each time-point.
2018-07-13 | E-MTAB-6975 | biostudies-arrayexpress
Project description:Using pharmacology and optogenetics perturbations, we showed that cortical brain-derived neurotrophic factor (BDNF) regulates the intensity of SWA via the activation of Tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We identified that the circuitry mediating TrkB-induced sleep SWA involves excitatory pyramidal cells of the cortex's layer 5. We found that increased neuronal firing alone in the somatosensory cortex was not sufficient to increase SWA. Using mathematical modeling of a local network in the brain, we model how BDNF’s effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Together, our findings implicate BDNF-TrkB-CREB signaling pathway in local SWA control during sleep.
2024-06-22 | PXD045652 | Pride
Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.
2022-09-20 | GSE190998 | GEO
Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration
2020-06-01 | GSE132534 | GEO
Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration
2020-06-01 | GSE132533 | GEO
Project description:Impaired angiogenesis characterized by the reduced proliferation of pulmonary endothelial cells leads to reduced capillary density in patients with bronchopulmonary dysplasia (BPD). In a mouse model of BPD, perinatal hyperoxic injury decreases the number of the recently identified lung capillary stem cells termed as general capillary (gCap) cells, along with the specific reduction of Ntrk2, which encodes for Tropomyosin receptor kinase B (TRKB) within this subpopulation. Herein, we determine whether TRKB signaling is required for perinatal gCap cell proliferation and further promoting pulmonary angiogenesis using the hyperoxia mouse BPD model. TRKB activation by BDNF treatment led to enhanced tube-forming ability of endothelial cells in vitro. In vivo treatment of mice with BDNF increased the proliferation of gCap cells and alleviated capillary loss caused by hyperoxic injury. Conversely, inhibition of TRKB signaling disrupted the tube formation of endothelial cells and exaggerated the vascular endothelial damage caused by hyperoxia. We further show that MAPK/ERK signaling might act downstream of TRKB to modulate pulmonary angiogenesis. These data indicate that TRKB signaling play a critical role in pulmonary angiogenesis upon perinatal lung injury, supporting the concept that TRKB activation might be a potential therapeutic for preserving endothelial cells for lung diseases associated with prematurity.
2024-09-15 | GSE276575 | GEO