Mus musculus strain:C57BL/6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA336455 | ENA |
REPOSITORIES: ENA
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Project description:Voluntary running triggers VGF-mediated oligodendrogenesis to prolong the lifespan of Snf2h-null ataxic mice
| PRJNA340987 | ENA
Project description:Exercise enhances cognitive function and slows progressive neurodegenerative disease. While exercise promotes neurogenesis, oligodendrogenesis and adaptive myelination are also significant contributors to brain repair and brain health. Nonetheless, the molecular details underlying these effects remain poorly understood. Conditional ablation of the Snf2h gene (Snf2h cKO) impairs cerebellar development producing mice with poor motor function, progressive ataxia and death between postnatal day 25 to 45. Here we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in hindbrain myelination and the long-term survival of Snf2h cKO mice. Further experiments identified the VGF growth factor as a major driver underlying this effect. VGF neuropeptides could promote oligodendrogenesis in vitro, while Snf2h cKO mice treated with full-length VGF-encoding adenoviruses obliterated the requirement of exercise for survival. Together, these results suggest that VGF delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the central nervous system.
2016-08-31 | GSE86235 | GEO
Project description:The neuropeptide VGF was recently proposed as a neurodegeneration biomarker. The Parkinson's disease-related protein leucine-rich repeat kinase 2 (LRRK2) regulates endolysosomal dynamics, a process that involves SNARE-mediated membrane fusion and could regulate secretion. Here we investigate potential biochemical and functional links between LRRK2 and v-SNAREs. We find that LRRK2 directly interacts with the v-SNAREs VAMP4 and VAMP7. Secretomics reveals VGF secretory defects in VAMP4 and VAMP7 knockout (KO) neuronal cells. In contrast, VAMP2 KO "regulated secretion-null" and ATG5 KO "autophagy-null" cells release more VGF. VGF is partially associated with extracellular vesicles and LAMP1+ endolysosomes. LRRK2 expression increases VGF perinuclear localization and impairs its secretion. Retention using selective hooks (RUSH) assays show that a pool of VGF traffics through VAMP4+ and VAMP7+ compartments, and LRRK2 expression delays its transport to the cell periphery. Overexpression of LRRK2 or VAMP7-longin domain impairs VGF peripheral localization in primary cultured neurons. Altogether, our results suggest that LRRK2 might regulate VGF secretion via interaction with VAMP4 and VAMP7.
2023-01-31 | PXD028321 | Pride
Project description:Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health 1. The natural polyamine spermidine has been linked to autophagy regulation, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders 2. Here, we report that spermidine levels increase upon acute fasting in yeast, flies, mice and healthy humans. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, worms and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan-extending, cardioprotective and antiarthritic effects of intermittent fasting. Mechanistically, spermidine mediated these effects via hypusination of the autophagy regulator eIF5A. In sum, the polyamine-hypusination axis thus emerges as a bona fide and phylogenetically conserved metabolic control hub for longevity and autophagy induction.
2024-04-30 | PXD035909 | Pride
Project description:Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Male C57BL/6J mice at 4 weeks of age were purchased from Shanghai Animal Co, Ltd. Mice were maintained under a 12-hour dark/light cycle (lights on at 6:30 am) at a temperature of 22 ± 3 °C in accredited animal facilities. Prior to the start of experiment, mice were maintained on a low-fat diet (Research Diets Inc., New Brunswick, NJ) for one week. At the age of 5 weeks, animals were randomly assigned to one of the 6 intervention groups (n = 30 for each group): feeding of a low-fat diet (10% fat, D12450B, Research Diets) ad libitum (LF) or with 30% calorie restriction (LF+CR) or with voluntary running exercise (LF+Ex), feeding of a high-fat diet (60% fat, D12492, Research Diets) ad libitum (HF) or with 30% calorie restriction (HF+CR) or with voluntary running exercise (HF+Ex). All mice were housed individually during the study. The daily consumption of food in LF and HF groups was recorded over a week and averaged to determine the amount of food for the following week for the LF+CR and HF+CR groups, respectively. After 1 week acclimation in cage with the locked running wheels, mice in the LF+Ex and HF+Ex groups were allowed free access to a running wheel, and the running distance and time were recorded automatically by the equipment. The hepatic transcriptional level for 3 mice from each intervention group at 62 weeks of age was analyzed using Affymetrix Mouse Genome 430 2.0 Arrays.
2012-03-27 | E-GEOD-36838 | biostudies-arrayexpress
Project description:Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, the telomere integrity is not only determined by telomere length but also by epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between telomere shortening-induced DDR and epigenetic modification in aging is unknown. Here we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs), and prolongs lifespan of late generation of telomerase deficient mice (G3Terc-/-). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin status for DDR signaling transduction through the demethylating of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a restores the heterochromatin compaction in the sub-telomeric regions and thereby ameliorating the DDR initiation at short telomeres of G3Terc-/- ISCs. Treatment with a small molecule inhibitor of BER alleviates DDR and improves the maintenance and function of G3Terc-/- ISCs. Taken together, our study discloses a potential therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modulating molecules.
2018-08-22 | GSE117845 | GEO
Project description:Remyelination is a multistep regenerative process that results in the reformation of myelin sheaths around demyelinated axons and is a critical therapeutic target. Here we show that immediate access to a running wheel following toxin-induced demyelination in mice enhances oligodendrogenesis, myelin thickness, and the proportion of remyelinated axons. RNA-sequencing suggests broad activation of pro-remyelination pathways including phagocytosis by exercise and highlights peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) activation. Our study demonstrates that physical activity is an integrative means to enhance remyelination and details a multimodal mechanism including the pivotal PGC1a-dependent enhancement of myelin thickness.
2018-08-16 | GSE118592 | GEO
Project description:Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasing β-cell replication. Here we show that Nkx6.1 strongly upregulates the prohormone VGF in rat islets and that VGF is both necessary and sufficient for Nkx6.1-mediated enhancement of GSIS. Moreover, the VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic injection of TLQP-21 in pre-diabetic ZDF rats preserves islet mass and slows diabetes onset. TLQP-21 prevents islet cell apoptosis by a pathway similar to that used by GLP-1, but independent of the GLP-1, GIP, or VIP receptors. Unlike GLP-1, TLQP-21 does not inhibit gastric emptying or increase heart rate. We conclude that a TLQP-21 is a novel agent for enhancing islet β-cell survival and function. We utilized a “sample x reference” experimental design strategy in which RNA extracted from rat pancreatic islets was hybridized to the microarray slide in the presence of labeled rat reference RNA (RRR, Stratagene, LaJolla, CA). Cultures were treated with adenoviruses expressing either the hamster form of Nkx6.1, the mouse form of Pdx1, or the beta-galactosidase enzyme. 3-5 biological replicates each representing independent islet isolations were used for microarray analysis. Briefly, five hundred nanograms of total RNA were used for gene expression profiling following reverse transcription and T-7 polymerase-mediated amplification/labeling with Cyanine-5. Labeled subject cRNA was co-hybridized to Operon rat 27K oligonucleotide arrays with equimolar amounts of Cyanine-3 labeled RRR. Slides were hybridized, washed, and scanned on a Gene Pix 5000 microarray scanner.
2012-05-09 | E-GEOD-37852 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest and most metastatic cancers in human. PDACs respond poorly to therapies, partly due to cancer stem cells (CSCs) that self-renew, survive chemotherapies, metastasise and replenish the tumour. Factors secreted by tumour cells mediate autocrine/paracrine crosstalk with surrounding cells contributing to the stem cell niche but are still insufficiently characterised. Here we used quantitative SILAC proteomics to identify secreted factors enriched in CSC secretome compared to non-CSCs. Among them were GDF15 and VGF, factors involved in cachexia and pain stimuli. GDF15 and VGF promoted CSC self-renewal and growth through autocrine effects. TGFβ/Activin signalling lowered GDF15 and VGF expression via SMAD2/3-SMAD4-SNON, switching to ATF4-CREB-mediated induction upon cell stress. Co-culture of PDAC-CSCs and hESC-derived neural cells for mimicking cellular crosstalk in PDAC revealed that paracrine signalling via GDF15/VGF promoted nociceptor formation and neurite outgrowth. In turn, Substance P from neurons supported CSC self-renewal, EMT/migration and clonal evolution that was also impacted by SMAD4 genetic status. Lastly, the serum levels of GDF15 and VGF were elevated in PDAC patients suggesting their utility as biomarkers for PDAC detection. Collectively, our data uncovered that cachexia and pain signalling factors mediate the crosstalk between CSCs and nociceptors.
2024-04-06 | PXD046026 | Pride
Project description:Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in regulating meiotic cell cycle progression. Females with oocyte-specific depletion of Snf2h are infertile and oocytes lacking Snf2h fail to undergo meiotic resumption. Mechanistically, depletion of Snf2h results in dysregulation of meiosis-related genes, which causes failure of maturation-promoting factor (MPF) activation. ATAC-seq analysis in oocytes revealed that Snf2h regulates transcription of a key meiotic gene, Prkar2b, by increasing its promoter chromatin accessibility. Our studies thus not only demonstrate the importance of Snf2h in oocyte meiotic resumption, but also reveal the mechanism underlying how a chromatin remodeling factor can regulate oocyte meiosis.
2020-01-19 | GSE134279 | GEO