Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA175398 | ENA |
REPOSITORIES: ENA
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Project description:Recent studies reported contradictory results regarding the role of ADP-ribosylation factor 6 (ARF6), a small GTPase known to regulate actin cytoskeleton, in dendritic spine development and maintenance. We readdress this question, and found that ARF6 either positively or negatively regulates dendritic spine formation depending on neuronal maturation and activity. ARF6 activation facilitates filopodia to spines transition, increasing the spine formation in developing neurons while it decreases spine density in matured neurons. Consistently, genome-wide microarray analysis revealed that Arf6 activation in developing and matured neurons leads to opposite expression patterns of a subset of genes that are involved in neuronal morphology.
2015-04-02 | GSE40937 | GEO
Project description:Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, cognitive deficits, and seizures, as well as potentially driving glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via ‘Ribotag’, morphometric analysis, and intravital imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden on excitatory neuronal pathophysiology as well as the impact of mTOR inhibition on these neuronal alterations. The Ribotag analysis of peritumoral excitatory neurons showed an upregulation in transcripts encoding for F-actin binding and other dendritic spine-enriched proteins. Light and electron microscopy analyses revealed marked decreases in dendritic spine density in peritumoral neurons. Intravital two-photon imaging in peritumoral excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single neuron level, throughout tumor growth. Intravital two-photon imaging also revealed altered stimulus-evoked somatic calcium activity, both in rate and temporal alignment, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a mTORC1 and mTORC2 inhibitor reversed the translational effect of glioma on neurons, increased dendritic spine density, and functional neuronal alterations. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma – manifested by alterations in ribosome-bound mRNA, dendritic spine morphology, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that peritumoral neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing foundational knowledge for developing therapies targeting neuronal signaling in glioma.
2024-01-30 | GSE254007 | GEO
Project description:Voluntary running exercise after focal cerebral ischemia promotes functional recovery and prevents the ischemia-induced dendritic spine loss in the peri-infarct motor cortex layer 5. Neuronal morphology is affected by the perineuronal environmental change. Glia exert crucial roles in the formation of perineuronal environment, and exercise-induced changes of glial phenotype are expected. Here, we demonstrated that voluntary running exercise increased the population of newborn astrocytes in the acute phase after cerebral ischemia at late phase. Transcriptome analysis detected 10 upregulated genes and 70 downregulated genes by exercise in the ipsilateral cortex astrocytes. Gene cluster downregulated by exercise were significantly associated with neuronal morphology. The expression of Lipocalin 2, a factor of decreasing dendritic spines, tended to be decreased in the postischemic astrocytes by exercise. Our results suggest that exercise modifies the phenotype of postischemic astrocytes, which relate to the exercise-induced amelioration of postischemic dendritic spine loss.
2022-08-08 | GSE210674 | GEO
Project description:We used genome-wide sequencing methods to study stimulus-dependent enhancer function in neurons. We identified ~12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Remarkably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 that is mono-methylated at lysine 4 (H3K4me1). The level of eRNA expression at neuronal enhancers positively correlates with the level of mRNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis. Examination of genome-wide binding of three types of modified histones, four transcription factors, and RNA polymerase II (ChIP-Seq), as well as RNA expression (RNA-Seq) before and after membrane depolarization via application of extracellular potassium.
2010-04-14 | E-GEOD-21161 | biostudies-arrayexpress
Project description:Mind bomb 1 (Mib1) is an E3 ubiquitin-ligase that is essential for overall metazoan development, including multiple stages of neuronal development. It is located in puncta throughout neurons, including near post synaptic densities (PSD), and has been shown to participate in several signaling pathways via its E3 ligase catalytic activity. The most well-characterized of these is the Notch signaling pathway, in which Mib1 facilitates Delta/Serrate/LAG-2 (DSL) ligand endocytosis and activation, allowing cell-cell communication to determine neuronal versus glial cell fate. This, however, is not the limit of Mib1 activity in the developing nervous system, as it also contributes to cell polarity, neurite outgrowth, and long-term potentiation (LTP), but it has not been demonstrated to affect dendritic spine development. We therefore sought to comprehensively characterize the Mib1 interactome and study its potential function in dendritic spine morphogenesis. We utilized a novel sequential elution method from Mib1 affinity purification to recover Mib1 binding proteins with both deep coverage and the ability to distinguish between high affinity binding partners from low affinity binding partners. This procedure revealed 837 potential binding partners, distinguished 72 from these as very-high confidence, and a further 387 as high confidence of interaction. Included in these were many proteins previously demonstrated to interact with Mib1, as well as 5 proteins of particular interest to us: Usp9x, a deubiquitinase; alpha-, beta-, and delta-catenins; regulators of Wnt signaling; and CDKL5, which is mutated in EIEE2, a severe form of mental retardation. We demonstrated that Mib1 downregulates CDKL5, limits its effects on dendritic spine outgrowth, and inhibits spine outgrowth itself. These data further elaborate upon the signaling networks and biological functions influenced by this critical protein and expand our understanding of the signaling networks involved in neuronal development.
2016-07-06 | PXD001255 | Pride
Project description:We provide a comprehensive map of the subcellular localization of mRNAs in mature neurons and reveal that transcripts stably retaining introns are broadly targeted for nuclear retention. We systematically probed the fate of nuclear transcripts upon neuronal stimulation and found that sub-populations of transcripts are bi-directionally regulated in response to neuronal cues: some are targeted for degradation while others undergo splicing completion to generate fully mature mRNAs which are exported to the cytosol.
2022-08-31 | GSE210071 | GEO
Project description:Flower maturation consists of several events that contribute to reproductive success as flowers open, including petal expansion, stamen filament elongation, pollen release, nectary maturation, stigma growth, and gynoecium maturation to support pollen tube growth. The Arabidopsis transcription factors ARF6 (Auxin Response Factor 6) and ARF8 regulate all of these processes, in part by activating jasmonate biosynthesis. Jasmonates in turn activate genes encoding the transcription factors MYB21 and MYB24, which mediate a subset of the processes controlled by ARF6 and ARF8. This experiment was designed to characterize gene expression in flowers before and after they open, and to determine how arf6 arf8 and myb21 myb24 mutation combinations affect these gene expression patterns. Three biological replicates were prepared at each of two developmental stages, stage 12 (oldest closed buds) and stage 13 (youngest open flowers), for three genotypes (Wild type, arf6-2 arf8-3, and myb21-5 myb24-5). For the mutant genotypes, stage 13 flowers do not actually open, so corresponding flowers of equivalent age were chosen based on the position of open flowers in wild-type inflorescences.
2011-12-10 | E-GEOD-32193 | biostudies-arrayexpress
Project description:We used genome-wide sequencing methods to study stimulus-dependent enhancer function in neurons. We identified ~12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Remarkably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 that is mono-methylated at lysine 4 (H3K4me1). The level of eRNA expression at neuronal enhancers positively correlates with the level of mRNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.
2010-04-15 | GSE21161 | GEO
Project description:Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that spine loss is induced by soluble, multimeric Ab42, whose post-synaptic signaling activates the protein phosphatase calcineurin. We investigated how calcineurin causes spine pathology and found that the cis-trans prolyl isomerase Pin1 is a critical downstream target of Ab42/calcineurin signaling. In spines, Pin1 interacts with and is dephosphorylated by calcineurin, which rapidly suppresses its isomerase activity. Pin1 knockout or Ab42 exposure induced mature spine loss in Ab42-treated wild-type cells but had no effect on Pin1 null neurons. The data implicate Pin1 in spine maintenance and synaptic loss in early Alzheimer's disease.
2018-02-14 | MSV000082066 | MassIVE
Project description:Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a novel mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine, and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.
2008-08-24 | GSE11939 | GEO