Prm2 deficiency triggers a Reactive Oxygen Species (ROS)-mediated destruction cascade during epididymal sperm maturation in mice
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PROVIDER: PRJNA628706 | ENA |
REPOSITORIES: ENA
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Project description:Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Prm2-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm`s antioxidant capacity, indicated by downregulation of key proteins like SOD1 and PRDX5, ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.
2020-07-29 | GSE149454 | GEO
Project description:MTD project_description Protamines are testis-specific proteins, which replace the majority of histones during spermiogenesis. This results in a hypercondensation of the sperm DNA, finally causing a conformational change from a nucleosomal chromatin structure into a mainly toroid like structure. This is assumed to protect the paternal genome and to contribute to the formation of a hydrodynamic sperm head shape. In mice and humans, two protamines, Protamine 1 (Prm1) and Protamine 2 (Prm2), are expressed. Impaired sperm protamination has been repeatedly correlated with male subfertility in mice and humans. Apart from defects in DNA condensation and impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary defects, which cannot be explained by the chromosomal function of protamines. These include impaired sperm motility, decreased viability as well as acrsosomal malformations. In this study, we utilized a Prm2-deficient mouse model to investigate the underlying molecular mechanisms of these defects. Since trancription is silenced upon incorporation of protamines, we used LC-MS in combination with label-free quantification to compare the sperm proteome of Prm2-deficient (Prm2-/-) males with the proteome of wildtype (Prm2+/+) and Prm2 heterozygous (Prm2+/-) males. We show that Prm2 deficient mice display a strongly altered proteomic profile compared to controls. Of note, a significant downregulation of proteins SOD1 and PRDX5, which have a well-known function for the detoxification of reactive oxygen species was observed. Thus, together with a series of additional experiments, we could for the first time show that Prm2-deficiency triggers a reactive oxygen species (ROS) mediated sperm destruction cascade during epididymal sperm maturation, finally causing described secondary sperm defects.
2020-07-29 | PXD018843 | Pride
Project description: Not available
| S-EPMC7463811 | biostudies-literature
Project description:Purpose: Although five receptors of RGF1 have recently been identified, the downstream signaling mechanism remains unknown. The goal of this study is to elucidate signaling events following RGF1 action. Methods: mRNA profiles of the root meristematic zone from Arabidopsis seedlings with or without RGF1 treatment were generated by deep sequencing, in triplicate. The sequence reads were analyzed using Tophat and DESeq2. The mutants of selected differentially expressed genes were generated for phenotyping. Results: Our study uncovered a series of signaling events following RGF1 action. The RGF1-receptor pathway controls distribution of reactive oxygen species (ROS) along the developmental zones of the Arabidopsis root. We identify a novel transcription factor, RGF1 INDUCIBLE TRANSCRIPTION FACTOR 1 (RITF1), which plays a central role in mediating RGF1 signaling. Manipulating RITF1 expression leads to redistribution of ROS along the root developmental zones. Changes in ROS distribution, in turn, enhance the stability of the PLETHORA2 (PLT2) protein, a master regulator of root stem cells. Conclusions: Our study clearly depicts a signaling cascade initiated by RGF1 and links the RGF1 peptide to ROS regulatory mechanisms.
2019-10-15 | GSE108730 | GEO
Project description:Human tumors often contain slowly proliferating cancer cells that resist treatment but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating “G0-like” progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur. 3 replicates each of MCF7 Reactive Oxygen Species (ROS) high, HCT116 ROS high, MCF7 ROS low, and HCT116 ROS low.
2011-07-14 | E-GEOD-30465 | biostudies-arrayexpress
Project description:Nutrient deprivation triggers the release of signal-sequence-lacking antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins, (Trx1 and Trx2) and peroxiredoxin Ahp1. Our data reveal that starvation increases mitochondrial activity, which generates higher, but non-toxic, levels of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS prevents antioxidants secretion. We suggest that in response to ROS production that can permeate the plasma membrane, the cells respond by secreting antioxidants to prevent ROS-mediated damage in the extracellular space. These findings provide an understanding of why cells secrete signal sequence lacking antioxidant enzymes in response to starvation.
2020-03-26 | PXD016815 | Pride
Project description:Signal-sequence-lacking superoxide dismutase 1 (SOD1) is secreted upon nutrient starvation, but the physiological relevance of this secretion is unclear. We now report that secreted SOD1 is functionally active. In addition, a secretome analysis has revealed number of other secreted cytoplasmic antioxidant enzymes, including both thioredoxins, (Trx1 and Trx2), and the peroxiredoxin Ahp1. Our data reveal that starvation triggers increased mitochondrial activity, leading to increased production of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS, inhibited secretion of the antioxidants. We suggest elevated ROS that evade cytoplasmic antioxidants, can permeate across the plasma membrane to the extracellular space. Cells secrete antioxidants to prevent ROS-mediated damage to the extracellular space. These findings thus provide an understanding of why cells secrete signal sequence lacking proteins like SOD1 and the larger family of antioxidants.
2019-05-14 | PXD010849 | Pride
Project description:Identification of ROS induced genes on dendritic cells Dendritic cells were incubated for 15 min with or without a ROS inhibitor (DPI), washed extensively and incubated for 30 min with a chemical allergen (DNFB), hydrogen peroxide, and vehicle alone in HBSS containing DPI or vehicle. After washed extensively, the samples were post-incubated for 5.5 h with DNFB, hydrogen peroxide, or vehicle in complete culture medium containing DPI or vehicle. Total RNA was extracted from cells treated with a chemical allergen, hydrogen peroxide, and vehicle alone in the presence or absence of a ROS inhibitor.
2011-03-10 | E-GEOD-20727 | biostudies-arrayexpress
Project description:In order to dissect the roles of sequence-specific transcription factors WRKY25, WRKY33 and WRKY75 in apoplastic ROS signaling, a transcriptome profiling of ozone response was done using two arabidopsis mutants: a double mutant wrky25 wrky33 and a single mutant wrky75. The single mutant lines used for transcriptomic analyses were obtained from NASC: wrky25 (SAIL_529_B11) and wrky33 (SALK_006603) were crossed to generate double mutant wrky25 wrky33. T-DNA insertion mutant wrky75-25 (N121525) was obtained from NASC. Three biological replicates, five plants per replicate, treated with 350 ppb ozone for 2 hours, were used for RNA-seq analysis. For each genotype, also non-ozone-treated samples were collected. For the Col-0 control line, an additional fourth replicate with/without ozone was done.
2016-04-03 | E-GEOD-79855 | biostudies-arrayexpress
Project description:Plants are essential for life on Earth converting light into chemical energy in the form of sugars. To adjust for changes in light intensity and quality, and to become as efficient as possible in harnessing light, plants evolved multiple light receptors, signaling, and acclimation mechanisms. In addition to altering plant metabolism, development and growth, light cues sensed by some photoreceptors, such as phytochromes, are also impacting many plant responses to biotic and abiotic stresses. Central for plant responses to different stresses are reactive oxygen species (ROS) that function as key signaling molecules. Recent studies demonstrated that respiratory burst oxidase homolog (RBOH) proteins that reside at the plasma membrane and produce ROS at the apoplast play a key role in plant responses to different biotic and abiotic stresses. Here we reveal that phytochrome B (phyB) and RBOHs function as part of a key regulatory module that controls ROS production, transcript expression, and plant acclimation to excess light stress. We further show that phyB can regulate ROS production during stress even if it is restricted to the cytosol, and that phyB, RBOHD and RBOHF co-regulate thousands of transcripts in response to light stress. Surprisingly, we found that phyB is also required for ROS accumulation in response to heat, wounding, cold, and bacterial infection. Taken together, our findings reveal that phyB plays a canonical role in plant responses to biotic and abiotic stresses, regulating ROS production, and that phyB and RBOHs function in the same regulatory pathway.
2022-05-31 | GSE188732 | GEO