scholarly journals Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression

2021 ◽  
Vol 13 ◽  
Author(s):  
Katarzyna M. Grochowska ◽  
Julia Bär ◽  
Guilherme M. Gomes ◽  
Michael R. Kreutz ◽  
Anna Karpova
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Protein Transport ◽  
Pyramidal Neurons ◽  
Temporal Integration ◽  
Dendritic Tree ◽  
Nuclear Gene ◽  
Receptor Activation ◽  
Excitatory Input ◽  
Splice Isoforms

Pyramidal neurons exhibit a complex dendritic tree that is decorated by a huge number of spine synapses receiving excitatory input. Synaptic signals not only act locally but are also conveyed to the nucleus of the postsynaptic neuron to regulate gene expression. This raises the question of how the spatio-temporal integration of synaptic inputs is accomplished at the genomic level and which molecular mechanisms are involved. Protein transport from synapse to nucleus has been shown in several studies and has the potential to encode synaptic signals at the site of origin and decode them in the nucleus. In this review, we summarize the knowledge about the properties of the synapto-nuclear messenger protein Jacob with special emphasis on a putative role in hippocampal neuronal plasticity. We will elaborate on the interactome of Jacob, the signals that control synapto-nuclear trafficking, the mechanisms of transport, and the potential nuclear function. In addition, we will address the organization of the Jacob/NSMF gene, its origin and we will summarize the evidence for the existence of splice isoforms and their expression pattern.

Perception and Signaling of Ultraviolet-B Radiation in Plants

2021 ◽  
Vol 72 (1) ◽  
Author(s):  
Roman Podolec ◽  
Emilie Demarsy ◽  
Roman Ulm
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Nuclear Gene ◽  
Feedback Regulation ◽  
Ultraviolet B ◽  
Photon Absorption ◽  
Annual Review ◽  
Publication Date ◽  
Negative Feedback Regulation ◽  
Nuclear Gene Expression

Ultraviolet-B (UV-B) radiation is an intrinsic fraction of sunlight that plants perceive through the UVR8 photoreceptor. UVR8 is a homodimer in its ground state that monomerizes upon UV-B photon absorption via distinct tryptophan residues. Monomeric UVR8 competitively binds to the substrate binding site of COP1, thus inhibiting its E3 ubiquitin ligase activity against target proteins, which include transcriptional regulators such as HY5. The UVR8–COP1 interaction also leads to the destabilization of PIF bHLH factor family members. Additionally, UVR8 directly interacts with and inhibits the DNA binding of a different set of transcription factors. Each of these UVR8 signaling mechanisms initiates nuclear gene expression changes leading to UV-B-induced photomorphogenesis and acclimation. The two WD40-repeat proteins RUP1 and RUP2 provide negative feedback regulation and inactivate UVR8 by facilitating redimerization. Here, we review the molecular mechanisms of the UVR8 pathway from UV-B perception and signal transduction to gene expression changes and physiological UV-B responses. Expected final online publication date for the Annual Review of Plant Biology, Volume 72 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach

2021 ◽  
Author(s):  
Jimmy Alarcan ◽  
Georges de Sousa ◽  
Efrosini S. Katsanou ◽  
Anastasia Spyropoulou ◽  
Petros Batakis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Receptor Activation ◽  
Adverse Outcome Pathway ◽  
Vitro Assay ◽  
Mixture Effects ◽  
Triglyceride Accumulation

AbstractWithin the EuroMix project, we have previously developed an adverse outcome pathway (AOP)-based in vitro assay toolbox to investigate the combined effects of liver steatosis-inducing compounds in human HepaRG hepatocarcinoma cells. In this study, we applied the toolbox to further investigate mixture effects of combinations, featuring either similarly acting or dissimilarly acting substances. The valproic acid structural analogs 2-propylheptanoic acid (PHP) and 2-propylhexanoic acid (PHX) were chosen for establishing mixtures of similarly acting substances, while a combination with the pesticidal active substance clothianidin (CTD) was chosen for establishing mixtures of dissimilarly acting compounds. We first determined relative potency factors (RPFs) for each compound based on triglyceride accumulation results. Thereafter, equipotent mixtures were tested for nuclear receptor activation in transfected HepG2 cells, while gene expression and triglyceride accumulation were investigated in HepaRG cells, following the proposed AOP for liver steatosis. Dose addition was observed for all combinations and endpoints tested, indicating the validity of the additivity assumption also in the case of the tested mixtures of dissimilarly acting substances. Gene expression results indicate that the existing steatosis AOP can still be refined with respect to the early key event (KE) of gene expression, in order to reflect the diversity of molecular mechanisms underlying the adverse outcome.

scholarly journals Chronic stress induces significant gene expression changes in the prefrontal cortex alongside alterations in adult hippocampal neurogenesis

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Ksenia Musaelyan ◽  
Selin Yildizoglu ◽  
James Bozeman ◽  
Andrea Du Preez ◽  
Martin Egeland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Chronic Stress ◽  
Molecular Mechanisms ◽  
Dendritic Tree ◽  
Hippocampal Neurogenesis ◽  
Stress Disorders ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Neurogenic Niche

Abstract Adult hippocampal neurogenesis is involved in stress-related disorders such as depression, posttraumatic stress disorders, as well as in the mechanism of antidepressant effects. However, the molecular mechanisms involved in these associations remain to be fully explored. In this study, unpredictable chronic mild stress in mice resulted in a deficit in neuronal dendritic tree development and neuroblast migration in the hippocampal neurogenic niche. To investigate molecular pathways underlying neurogenesis alteration, genome-wide gene expression changes were assessed in the prefrontal cortex, hippocampus and the hypothalamus alongside neurogenesis changes. Cluster analysis showed that the transcriptomic signature of chronic stress is much more prominent in the prefrontal cortex compared to the hippocampus and the hypothalamus. Pathway analyses suggested huntingtin, leptin, myelin regulatory factor, methyl-CpG binding protein and brain-derived neurotrophic factor as the top predicted upstream regulators of transcriptomic changes in the prefrontal cortex. Involvement of the satiety regulating pathways (leptin) was corroborated by behavioural data showing increased food reward motivation in stressed mice. Behavioural and gene expression data also suggested circadian rhythm disruption and activation of circadian clock genes such as Period 2. Interestingly, most of these pathways have been previously shown to be involved in the regulation of adult hippocampal neurogenesis. It is possible that activation of these pathways in the prefrontal cortex by chronic stress indirectly affects neuronal differentiation and migration in the hippocampal neurogenic niche via reciprocal connections between the two brain areas.

Systems Approach to Integrating Preclinical Apolipoprotein E-Knockout Investigations Reveals Novel Etiologic Pathways and Master Atherosclerosis Network in Humans

2021 ◽  
Author(s):  
Megan M. Shuey ◽  
Rachel R. Xiang ◽  
M. Elizabeth Moss ◽  
Brigett V. Carvajal ◽  
Yihua Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Apolipoprotein E ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Systems Approach ◽  
Human Subjects ◽  
Strong Association ◽  
Human Study ◽  
Receptor Activation ◽  
Retinoid Receptor

Objective: Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach to integration of preclinical data identifies novel pathways and regulators in human disease. Approach and Results: Of 716 articles published in ATVB from 1995 to 2019 using the apolipoprotein E knockout mouse to study atherosclerosis, data were extracted from 360 unique studies in which a gene was experimentally perturbed to impact plaque size or composition and analyzed using Ingenuity Pathway Analysis software. TREM1 (triggering receptor expressed on myeloid cells) signaling and liver×receptor/retinoid×receptor activation were identified as the top atherosclerosis-associated pathways in mice (both P <1.93×10 − 4 , TREM1 implicated early and liver×receptor/retinoid×receptor in late atherogenesis). The top upstream regulatory network in mice (sc-58125, a COX2 inhibitor) linked 64.0% of the genes into a single network. The pathways and networks identified in mice were interrogated by testing for associations between the genetically predicted gene expression of each mouse pathway-identified human homolog with clinical atherosclerosis in a cohort of 88 660 human subjects. Homologous human pathways and networks were significantly enriched for gene-atherosclerosis associations (empirical P <0.01 for TREM1 and liver×receptor/retinoid×receptor pathways and COX2 network). This included 12(60.0%) TREM1 pathway genes, 15(53.6%) liver×receptor/retinoid×receptor pathway genes, and 67(49.3%) COX2 network genes. Mouse analyses predicted, and human study validated, the strong association of COX2 expression ( PTGS2 ) with increased likelihood of atherosclerosis (odds ratio, 1.68 per SD of genetically predicted gene expression; P =1.07×10 − 6 ). Conclusions: Preclinical Science Integration and Translation leverages published preclinical investigations to identify high-confidence pathways, networks, and regulators of human disease.

scholarly journals Neurexins regulate presynaptic GABAB-receptors at central synapses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fujun Luo ◽  
Alessandra Sclip ◽  
Sean Merrill ◽  
Thomas C. Südhof
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Inhibitory Synapses ◽  
Receptor Signaling ◽  
Ca1 Region ◽  
Presynaptic Active Zone

AbstractDiverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABAB-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABAB-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABAB-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABAB-receptor activation. Moreover, deletion of neurexins caused a loss of GABAB-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABAB-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

scholarly journals The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury

2020 ◽  
Vol 31 (4) ◽  
pp. 716-730 ◽  
Author(s):  
Marc Johnsen ◽  
Torsten Kubacki ◽  
Assa Yeroslaviz ◽  
Martin Richard Späth ◽  
Jannis Mörsdorf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reperfusion Injury ◽  
Caloric Restriction ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxic Preconditioning ◽  
Preventive Strategies ◽  
Gene Expression Signatures

BackgroundAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance.MethodsTo identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury.ResultsThe gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI.ConclusionsThis comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

scholarly journals Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bastiaan van der Veen ◽  
Sampath K. T. Kapanaiah ◽  
Kasyoka Kilonzo ◽  
Peter Steele-Perkins ◽  
Martin M. Jendryka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Anterior Cingulate Cortex ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Pyramidal Neurons ◽  
Treatment Options ◽  
Pyramidal Cells ◽  
Cingulate Cortex ◽  
Cell Types ◽  
Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

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