scholarly journals The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development

2013 ◽  
Vol 201 (6) ◽  
pp. 929-944 ◽  
Author(s):  
Jooyeon Woo ◽  
Seok-Kyu Kwon ◽  
Jungyong Nam ◽  
Seungwon Choi ◽  
Hideto Takahashi ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Synapse Formation ◽  
Super Resolution ◽  
Protein S ◽  
Inhibitory Synapses ◽  
Synaptic Organization ◽  
Adhesion Protein ◽  
Resolution Imaging ◽  
Homophilic Adhesion

Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABAA receptor– and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABAA receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2.

scholarly journals Selective Upregulation of Endothelial E-Selectin in Response to Helicobacter pylori-Induced Gastritis

2009 ◽  
Vol 77 (7) ◽  
pp. 3109-3116 ◽  
Author(s):  
Helena Svensson ◽  
Malin Hansson ◽  
Jan Kilhamn ◽  
Steffen Backert ◽  
Marianne Quiding-Järbrink
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Adhesion Protein ◽  
Type Iv ◽  
Endothelial Adhesion Molecules ◽  
H Pylori ◽  
Vascular Adhesion

ABSTRACT Helicobacter pylori is one of the most common bacterial pathogens, infecting up to 50% of the world's population. The host is not able to clear the infection, leading to life-long chronic inflammation with continuous infiltration of lymphocytes and granulocytes. The migration of leukocytes from the blood into inflamed tissue is dependent on adhesion molecules expressed on the vascular endothelium. The aim of this study was to characterize the effect of H. pylori-induced gastritis with regard to the expression of endothelial adhesion molecules in the gastric mucosa and compare this to other types of chronic mucosal inflammations. Our results demonstrate an increased level of expression of the adhesion molecule E-selectin, but not of intracellular adhesion molecule 1, vascular adhesion molecule 1, or vascular adhesion protein 1, in H. pylori-induced gastritis but not in gastritis induced by acetylsalicylic acid or pouchitis. The upregulated E-selectin expression was determined to be localized to the gastric mucosa rather than being a systemic response to the infection. Moreover, the H. pylori type IV secretion system encoded by the cag pathogenicity island (cagPAI) was found to be an important determinant for the upregulation of human endothelial E-selectin expression in vitro, and this process is probably dependent on the CagL protein, mediating binding to α5β1 integrins. Thus, endothelial E-selectin expression induced by H. pylori probably contributes to the large influx of neutrophils and macrophages seen in infected individuals, and our results suggest that this process may be more pronounced in patients infected with cagPAI-positive H. pylori strains and may thereby contribute to tissue damage in these individuals.

scholarly journals Proteomic and functional analyses of the periodic membrane skeleton in neurons

2020 ◽  
Author(s):  
Ruobo Zhou ◽  
Boran Han ◽  
Roberta Nowak ◽  
Yunzhe Lu ◽  
Evan Heller ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Super Resolution ◽  
Membrane Skeleton ◽  
Interacting Proteins ◽  
Functional Roles ◽  
Genetic Perturbations ◽  
Resolution Imaging ◽  
Functional Analyses

AbstractActin, spectrin, and associated molecules form a membrane-associated periodic skeleton (MPS) in neurons. The molecular composition and functions of the MPS remain incompletely understood. Here, using co-immunoprecipitation and mass spectrometry, we identified hundreds of candidate MPS-interacting proteins that span diverse functional categories. We validated representative proteins in several of these categories, including previously unknown MPS structural components, as well as motor proteins, cell adhesion molecules, ion channels, and signaling proteins, demonstrating periodic distributions of ∼20 proteins in neurons using super-resolution imaging. Genetic perturbations of the MPS and its interacting proteins further suggested functional roles of the MPS in axon-axon and axon-dendrite interactions and in axon diameter regulation, and implicated the involvement of MPS interactions with cell adhesion molecules and non-muscle myosin in these roles. These results provide new insights into the interactome of the MPS, and suggest new functions of the MPS in neurons.

scholarly journals Transsynaptic N-Cadherin Adhesion Complexes Control Presynaptic Vesicle and Bulk Endocytosis at Physiological Temperature

2021 ◽  
Vol 15 ◽  
Author(s):  
Sushma Dagar ◽  
Zenghui Teng ◽  
Kurt Gottmann
Keyword(s):  
Actin Polymerization ◽  
Super Resolution ◽  
Glutamatergic Synapses ◽  
Physiological Regulation ◽  
Adhesion Protein ◽  
Physiological Temperature ◽  
Presynaptic Vesicle ◽  
Efficient Coupling ◽  
And Function ◽  
Homophilic Adhesion

At mammalian glutamatergic synapses, most basic elements of synaptic transmission have been shown to be modulated by specific transsynaptic adhesion complexes. However, although crucial for synapse homeostasis, a physiological regulation of synaptic vesicle endocytosis by adhesion molecules has not been firmly established. The homophilic adhesion protein N-cadherin is localized at the peri-active zone, where the highly temperature-dependent endocytosis of vesicles occurs. Here, we demonstrate an important modulatory role of N-cadherin in endocytosis at near physiological temperature by synaptophysin-pHluorin imaging. Different modes of endocytosis including bulk endocytosis were dependent on N-cadherin expression and function. N-cadherin modulation might be mediated by actin filaments because actin polymerization ameliorated the knockout-induced endocytosis defect. Using super-resolution imaging, we found strong recruitment of N-cadherin to glutamatergic synapses upon massive vesicle release, which might in turn enhance vesicle endocytosis. This provides a novel, adhesion protein-mediated mechanism for efficient coupling of exo- and endocytosis.

scholarly journals Synaptic accumulation of FUS triggers age-dependent misregulation of inhibitory synapses in ALS-FUS mice

2020 ◽  
Author(s):  
Sonu Sahadevan ◽  
Katharina M. Hembach ◽  
Elena Tantardini ◽  
Manuela Pérez-Berlanga ◽  
Marian Hruska-Plochan ◽  
...  
Keyword(s):  
Rna Binding ◽  
Super Resolution ◽  
Inhibitory Synapses ◽  
Rna Seq ◽  
Rna Targets ◽  
Pathological Mechanism ◽  
Age Dependent ◽  
Gabaergic Synapses ◽  
Resolution Imaging ◽  
Lateral Sclerosis

AbstractFUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages, accompanied by alterations in density and size of GABAergic synapses. RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS accumulation at the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.

Tools and limitations to study the molecular composition of synapses by fluorescence microscopy

2016 ◽  
Vol 473 (20) ◽  
pp. 3385-3399 ◽  
Author(s):  
Manuel Maidorn ◽  
Silvio O. Rizzoli ◽  
Felipe Opazo
Keyword(s):  
Super Resolution ◽  
Molecular Composition ◽  
Synaptic Organization ◽  
Synaptic Physiology ◽  
Copy Numbers ◽  
Resolution Imaging ◽  
And Function ◽  
Microscopy Techniques ◽  
Super Resolution Microscopy ◽  
Affinity Probes

The synapse is densely packed with proteins involved in various highly regulated processes. Synaptic protein copy numbers and their stoichiometric distribution have a drastic influence on neuronal integrity and function. Therefore, the molecular analysis of synapses is a key element to understand their architecture and function. The overall structure of the synapse has been revealed with an exquisite amount of details by electron microscopy. However, the molecular composition and the localization of proteins are more easily addressed with fluorescence imaging, especially with the improved resolution achieved by super-resolution microscopy techniques. Notably, the fast improvement of imaging instruments has not been reflected in the optimization of biological sample preparation. During recent years, large efforts have been made to generate affinity probes smaller than conventional antibodies adapted for fluorescent super-resolution imaging. In this review, we briefly discuss the current views on synaptic organization and necessary key technologies to progress in the understanding of synaptic physiology. We also highlight the challenges faced by current fluorescent super-resolution methods, and we describe the prerequisites for an ideal study of synaptic organization.

scholarly journals Transsynaptic N-cadherin adhesion complexes control presynaptic vesicle and bulk endocytosis at physiological temperature

2021 ◽  
Author(s):  
Sushma Dagar ◽  
Kurt Gottmann
Keyword(s):  
Actin Polymerization ◽  
Super Resolution ◽  
Glutamatergic Synapses ◽  
Physiological Regulation ◽  
Adhesion Protein ◽  
Physiological Temperature ◽  
Presynaptic Vesicle ◽  
Efficient Coupling ◽  
And Function ◽  
Homophilic Adhesion

AbstractAt mammalian glutamatergic synapses, most basic elements of synaptic transmission have been shown to be modulated by specific transsynaptic adhesion complexes. However, although crucial for synapse homeostasis, a physiological regulation of synaptic vesicle endocytosis by adhesion molecules has not been firmly established. The homophilic adhesion protein N-cadherin is localized at the peri-active zone, where the highly temperature dependent endocytosis of vesicles occurs. Here, we demonstrate an important modulatory role of N-cadherin in endocytosis at near physiological temperature by synaptophysin-pHluorin imaging. Different modes of endocytosis including bulk endocytosis were dependent on N-cadherin expression and function. N-cadherin modulation was mediated by actin filaments, because actin polymerization rescued the knockout induced endocytosis defect. Using super-resolution imaging, we found a strong recruitment of N-cadherin to glutamatergic synapses upon massive vesicle release, which might in turn enhance vesicle endocytosis. This provides a novel, adhesion protein mediated mechanism for efficient coupling of exo- and endocytosis.

scholarly journals Differential homeostatic regulation of glycinergic and GABAergic nanocolumns at mixed inhibitory synapses

2020 ◽  
Author(s):  
Xiaojuan Yang ◽  
Hervé Le Corronc ◽  
Pascal Legendre ◽  
Antoine Triller ◽  
Christian G Specht
Keyword(s):  
Spatial Organization ◽  
Super Resolution ◽  
Scaffold Protein ◽  
Synaptic Proteins ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Homeostatic Regulation ◽  
Synaptic Organization ◽  
Spinal Cord Neurons ◽  
Activity Dependent

AbstractSuper-resolution imaging of synapses has revealed that key synaptic proteins are dynamically organized within sub-synaptic domains (SSDs). At mixed inhibitory synapses in spinal cord neurons, both GlyRs and GABAARs reside at the same post-synaptic density (PSD). To examine how the different inhibitory receptors are organized and regulated, we carried out dual-color direct stochastic optical reconstruction microscopy (dSTORM). We found that endogenous GlyRs and GABAARs as well as their common scaffold protein gephyrin form SSDs that align with pre-synaptic RIM1/2, thus forming trans-synaptic nanocolumns. Strikingly, GlyRs and GABAARs occupy different sub-synaptic spaces, exhibiting only a partial overlap at mixed inhibitory synapses. When network activity was increased by pharmacological treatment using the K+ channel blocker 4-aminopyridine (4-AP), the GABAAR copy numbers of as well as the number of GABAAR SSDs were reduced, while GlyRs remained largely unchanged. This differential regulation is likely the result of changes in gephyrin phosphorylation that preferentially occurred outside of the SSDs. The total gephyrin content was not altered by 4-AP application. The activity-dependent regulation of GABAARs versus GlyRs suggests that different signaling pathways control their respective sub-synaptic organization. Whereas gephyrin serves as a scaffold protein that upholds GlyR numbers at SSDs, it may act as a switch regulating GABAARs via its phosphorylation state. Taken together, our data reinforce the notion that the precise sub-synaptic organization of GlyRs, GABAARs and gephyrin has functional consequences for the homeostatic regulation of mixed inhibitory synapses.HighlightsAlignment of sub-synaptic domains (SSDs) in trans-synaptic nanocolumns at inhibitory synapses Differential spatial organization of SSDs formed by GlyRs and GABAARs at mixed inhibitory synapses Activity-dependent regulation of GABAARs but not GlyRs at mixed inhibitory synapses Gephyrin phosphorylation is compartmentalized in SSDs within the synaptic scaffold

scholarly journals Calsyntenin-3, an atypical cadherin, suppresses inhibitory basket- and stellate-cell synapses but boosts excitatory parallel-fiber synapses in cerebellum

2021 ◽  
Author(s):  
Zhihui Liu ◽  
Man Jiang ◽  
Kif Liakath-Ali ◽  
Jaewon Ko ◽  
Roger Shen Zhang ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Adhesion Molecule ◽  
Synapse Formation ◽  
Stellate Cell ◽  
Parallel Fiber ◽  
Inhibitory Synapses ◽  
New Paradigm ◽  
Synaptic Regulation ◽  
Cerebellar Purkinje Cells

Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic adaptors for kinesin-mediated vesicular transport. Here, we show that acute CRISPR-mediated deletion of calsyntenin-3 in cerebellar Purkinje cells in vivo causes a large decrease in inhibitory synapses, but a surprisingly robust increase in excitatory parallel-fiber synapses. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Thus, by promoting formation of an excitatory type of synapses and decreasing formation of an inhibitory type of synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells. No similarly opposing function of a synaptic adhesion molecule was previously observed, suggesting a new paradigm of synaptic regulation.

scholarly journals A B cell actomyosin arc network couples integrin co-stimulation to mechanical force-dependent immune synapse formation

2021 ◽  
Author(s):  
Jia C Wang ◽  
Yang-In Yim ◽  
Xufeng Wu ◽  
Valentin Jaumouillé ◽  
Clare M Waterman ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Synapse Formation ◽  
Super Resolution ◽  
Cell Receptor ◽  
B Cell Activation ◽  
Protein Distribution ◽  
Immune Synapse ◽  
Resolution Imaging ◽  
Membrane Bound

B-cell activation and immune synapse (IS) formation with membrane-bound antigens are actin-dependent processes that scale positively with the strength of antigen-induced signals. Importantly, ligating the B-cell integrin, LFA-1, with ICAM-1 promotes IS formation when antigen is limiting. Whether the actin cytoskeleton plays a specific role in integrin-dependent IS formation is unknown. Here we show using super-resolution imaging of primary B cells that LFA-1: ICAM-1 interactions promote the formation of an actomyosin network that dominates the B-cell IS. This network is created by the formin mDia1, organized into concentric, contractile arcs by myosin 2A, and flows inward at the same rate as B-cell receptor (BCR): antigen clusters. Consistently, individual BCR microclusters are swept inward by individual actomyosin arcs. Under conditions where integrin is required for synapse formation, inhibiting myosin impairs synapse formation, as evidenced by reduced antigen centralization, diminished BCR signaling, and defective signaling protein distribution at the synapse. Together, these results argue that a contractile actomyosin arc network plays a key role in the mechanism by which LFA-1 co-stimulation promotes B-cell activation and IS formation.

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