ARF6 bi-directionally regulates the dendritic spine formation depending on neuronal maturation and activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE40937 | GEO | 2015/04/02
SECONDARY ACCESSION(S): PRJNA175398
REPOSITORIES: GEO
Similar Datasets
Project description:Autophagic and endosomal dysfunctions are prominently observed at preclinical stages of Alzheimer's disease (AD) as well as in presenilin (PSEN) 1-deficient mice and neurons. In the latter, the defects relate to the γ-secretase-independent role of PSEN in lysosomal fusion and organelle turnover. While we demonstrated previously that the impaired capacity of lysosomal fusion is associated with a significant reduction in lysosomal calcium storage/release, the underlying mechanism remained unexplored. Here we demonstrate that PSEN-deficient cells are impaired in endosomal recycling of several cargo proteins reminiscent of clathrin-independent carriers and lipid rafts. This is accompanied by the accumulation of cholesterol in LAMP1-positive organelles. The small GTPase ARF6, an important regulator of lipid raft recycling, fully rescues the endo-lysosomal abnormalities in PSEN-/- cells, suggesting that defective recycling is upstream of lysosomal dysfunction. PSEN-/- cells and neurons present significantly reduced ARF6 expression levels. Importantly, similar decreased ARF6 levels are observed in aging murine neurons and brain and are even more pronounced in AD brains, suggesting a particular vulnerability of ARF6-mediated recycling in the early etiology of AD.
2017-12-15 | GSE44454 | GEO
Project description:Excitatory synapses of principal hippocampal neurons are frequently located on dendritic spines. The dynamic strengthening or weakening of individual inputs results in a great structural and molecular diversity of dendritic spines. Active spines with large Ca2+-transients are frequently invaded by a single protrusion from the endoplasmic reticulum (ER), which is dynamically transported into spines by the actin-based motor myosin V. An increase in synaptic strength often correlates with stable anchoring of the ER, followed by the formation of the spine apparatus organelle. Here we characterize the newly identified interaction of myosin V with the Ca2+-sensor caldendrin, a brain-specific homolog of the well-known myosin V interactor calmodulin. While calmodulin is an essential activator of myosin V motor function, we found that caldendrin acts as an inhibitor of processive myosin V movement. We propose that caldendrin transforms myosin into a stationary F actin tether, and show that in mouse and rat hippocampal neurons, caldendrin regulates spine apparatus localization to a subset of dendritic spines through a myosin V-dependent pathway.
2022-01-27 | PXD029427 | Pride
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: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:The aim of this study was to examine the roles of Auxin Response Factors (ARFs) in flower gene expression. Flowers from arf6 arf8 plants undergo a developmental arrest at approximately stage 12, just prior to flower opening. Wild-type, ARF6/arf6 arf8/arf8, and arf6 arf8 plants were treated with 10 uM indole-3-acetic acid for thirty minutes to identify genes that respond rapidly to auxin in an ARF6/ARF8-dependent manner. Keywords: auxin response; comparison of wild type and arf6 arf8 mutants
2005-06-30 | GSE2847 | GEO
Project description:The aim of this study was to examine the contribution of ARF6 and ARF8 to flower gene expression. Flowers from arf6 arf8 plants undergo a developmental arrest at approximately stage 12, just prior to flower opening. Flowers from wild-type, arf6/arf6 ARF8/arf8, and arf6 arf8 plants were separated into stage 1-10 flowers, stage 11+12 flowers, and stage 13-14 flowers to define the developmental stages at which ARF6 and ARF8 are required for gene expression.
2007-06-28 | E-GEOD-2848 | biostudies-arrayexpress
Project description:Arf6 is a small GTPase regulating many cellular processes including cytoskeletal remodeling, receptor endocytosis, and phagocytosis of pathogens. Arf6 knockdown in neutrophil (PMN)-like cells was reported to inhibit chemotactic peptide-mediated activation of phospholipase D, the oxidative burst, and 2 integrin-dependent adhesion. In mice, the migration of PMNs knock out for Arf6 to the site of inflammation was diminished and associated with reduced cell surface expression of 2 integrins. Conditional knockout mice lacking Arf6 in PMNs were used to assess the impact of Arf6 depletion on the functions and gene expression profile of PMNs isolated from the mouse air pouch injected with lipopolysaccharide (LPS). The expression of several genes was modulated in PMNs-Arf6 cKO with Lpar6 and Lacc-1 being the most up-regulated and down-regulated genes, respectively. Decreased expressed of Lacc-1 was validated at the protein level in PMN-Arf6 cKO, and silencing of Arf6 in THP-1 monocytic cells delayed LPS-mediated Lacc-1 expression. Here we report that fMLP or zymosan-induced glycolysis and oxygen consumption rate were decreased in air pouch PMNs but not in BM PMNs of Arf6 cKO mice when compared to control floxed cells. Reduced oxygen consumption correlated with decreased production of superoxide and ROS. Depletion of Arf6 in mouse PMNs also reduced phagocytosis and interfered apoptosis. The data suggest that Arf6 regulates energy metabolism, which may contribute to impaired phagocytosis, ROS production, and apoptosis in PMN-Arf6 cKO. This study provides new information on the functions and the inflammatory pathways influenced by Arf6 in PMNs.
2021-05-28 | GSE151436 | GEO
Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses. After 10 days in culture, dissociated mouse hippocampal neurons in 6-well plates were infected with lentivirus expressing either Flag-Nr4a1 or GFP and incubated for 6 days to allow for transgene expression. Total RNA was then isolated using RNeasy Plus kit (QIAGEN). Samples passing an mRNA quality check proceeded to quantitative analysis on Agilent-026655 4x44 Mouse Microarrays.
2016-01-13 | E-GEOD-76805 | biostudies-arrayexpress
Project description:The aim of this study was to examine the roles of Auxin Response Factors (ARFs) in flower gene expression. Flowers from arf6 arf8 plants undergo a developmental arrest at approximately stage 12, just prior to flower opening. Wild-type, ARF6/arf6 arf8/arf8, and arf6 arf8 plants were treated with 10 uM indole-3-acetic acid for thirty minutes to identify genes that respond rapidly to auxin in an ARF6/ARF8-dependent manner. Experiment Overall Design: Wild-type, ARF6/arf6 arf8/arf8, and arf6 arf8 plants were sprayed with 10 mM indole-3-acetic acid in 1% methanol, 0.05% Tween-20. Thirty minutes after treatment, flowers (stage 1-14) were collected, frozen in liquid nitrogen, and used for RNA extraction.
2007-07-11 | E-GEOD-2847 | biostudies-arrayexpress
Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses.
2016-01-13 | GSE76805 | GEO