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  1. Article: SNARE-Mediated Exocytosis in Neuronal Development.

    Urbina, Fabio L / Gupton, Stephanie L

    Frontiers in molecular neuroscience

    2020  Volume 13, Page(s) 133

    Abstract: The formation of the nervous system involves establishing complex networks of synaptic connections between proper partners. This developmental undertaking requires the rapid expansion of the plasma membrane surface area as neurons grow and polarize, ... ...

    Abstract The formation of the nervous system involves establishing complex networks of synaptic connections between proper partners. This developmental undertaking requires the rapid expansion of the plasma membrane surface area as neurons grow and polarize, extending axons through the extracellular environment. Critical to the expansion of the plasma membrane and addition of plasma membrane material is exocytic vesicle fusion, a regulated mechanism driven by soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNAREs). Since their discovery, SNAREs have been implicated in several critical neuronal functions involving exocytic fusion in addition to synaptic transmission, including neurite initiation and outgrowth, axon specification, axon extension, and synaptogenesis. Decades of research have uncovered a rich variety of SNARE expression and function. The basis of SNARE-mediated fusion, the opening of a fusion pore, remains an enigmatic event, despite an incredible amount of research, as fusion is not only heterogeneous but also spatially small and temporally fast. Multiple modes of exocytosis have been proposed, with full-vesicle fusion (FFV) and kiss-and-run (KNR) being the best described. Whereas most
    Language English
    Publishing date 2020-08-07
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2020.00133
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Spatiotemporal organization of exocytosis emerges during neuronal shape change.

    Urbina, Fabio L / Gomez, Shawn M / Gupton, Stephanie L

    The Journal of cell biology

    2018  Volume 217, Issue 3, Page(s) 1113–1128

    Abstract: Neurite elongation and branching in developing neurons requires plasmalemma expansion, hypothesized to occur primarily via exocytosis. We posited that exocytosis in developing neurons and nonneuronal cells would exhibit distinct spatiotemporal ... ...

    Abstract Neurite elongation and branching in developing neurons requires plasmalemma expansion, hypothesized to occur primarily via exocytosis. We posited that exocytosis in developing neurons and nonneuronal cells would exhibit distinct spatiotemporal organization. We exploited total internal reflection fluorescence microscopy to image vesicle-associated membrane protein (VAMP)-pHluorin-mediated exocytosis in mouse embryonic cortical neurons and interphase melanoma cells, and developed computer-vision software and statistical tools to uncover spatiotemporal aspects of exocytosis. Vesicle fusion behavior differed between vesicle types, cell types, developmental stages, and extracellular environments. Experiment-based mathematical calculations indicated that VAMP2-mediated vesicle fusion supplied excess material for the plasma membrane expansion that occurred early in neuronal morphogenesis, which was balanced by clathrin-mediated endocytosis. Spatial statistics uncovered distinct spatiotemporal regulation of exocytosis in the soma and neurites of developing neurons that was modulated by developmental stage, exposure to the guidance cue netrin-1, and the brain-enriched ubiquitin ligase tripartite motif 9. In melanoma cells, exocytosis occurred less frequently, with distinct spatial clustering patterns.
    MeSH term(s) Animals ; Axon Guidance/drug effects ; Axon Guidance/physiology ; Carrier Proteins/genetics ; Cell Line, Tumor ; Cell Shape ; Clathrin/genetics ; Clathrin/metabolism ; Exocytosis/drug effects ; Exocytosis/physiology ; HEK293 Cells ; Humans ; Image Processing, Computer-Assisted ; Mice ; Mice, Knockout ; Nerve Tissue Proteins/genetics ; Netrin-1/pharmacology ; Neurites/drug effects ; Neurites/physiology ; Neurogenesis ; Neurons/cytology ; Neurons/drug effects ; Neurons/physiology ; Primary Cell Culture ; Software ; Ubiquitin-Protein Ligases ; Vesicle-Associated Membrane Protein 2/metabolism
    Chemical Substances Carrier Proteins ; Clathrin ; Nerve Tissue Proteins ; Vesicle-Associated Membrane Protein 2 ; Netrin-1 (158651-98-0) ; Trim9 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2018-01-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201709064
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: TRIM67 regulates exocytic mode and neuronal morphogenesis via SNAP47.

    Urbina, Fabio L / Menon, Shalini / Goldfarb, Dennis / Edwards, Reginald / Ben Major, M / Brennwald, Patrick / Gupton, Stephanie L

    Cell reports

    2022  Volume 34, Issue 6, Page(s) 108743

    Abstract: Neuronal morphogenesis involves dramatic plasma membrane expansion, fueled by soluble N-ethylmaleimide-sensitive factor attachment protein eceptors (SNARE)-mediated exocytosis. Distinct fusion modes described at synapses include full-vesicle fusion (FVF) ...

    Abstract Neuronal morphogenesis involves dramatic plasma membrane expansion, fueled by soluble N-ethylmaleimide-sensitive factor attachment protein eceptors (SNARE)-mediated exocytosis. Distinct fusion modes described at synapses include full-vesicle fusion (FVF) and kiss-and-run fusion (KNR). During FVF, lumenal cargo is secreted and vesicle membrane incorporates into the plasma membrane. During KNR, a transient fusion pore secretes cargo but closes without membrane addition. In contrast, fusion modes are not described in developing neurons. Here, we resolve individual exocytic events in developing murine cortical neurons and use classification tools to identify four distinguishable fusion modes: two FVF-like modes that insert membrane material and two KNR-like modes that do not. Discrete fluorescence profiles suggest distinct behavior of the fusion pore. Simulations and experiments agree that FVF-like exocytosis provides sufficient membrane material for morphogenesis. We find the E3 ubiquitin ligase TRIM67 promotes FVF-like exocytosis in part by limiting incorporation of the Qb/Qc SNARE SNAP47 into SNARE complexes and, thus, SNAP47 involvement in exocytosis.
    MeSH term(s) Animals ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; Exocytosis ; Female ; Mice ; Mice, Knockout ; Neurogenesis ; Qb-SNARE Proteins/genetics ; Qb-SNARE Proteins/metabolism ; Qc-SNARE Proteins/genetics ; Qc-SNARE Proteins/metabolism ; SNARE Proteins/genetics ; SNARE Proteins/metabolism ; Synapses/genetics ; Synapses/metabolism ; Tripartite Motif Proteins/genetics ; Tripartite Motif Proteins/metabolism
    Chemical Substances Cytoskeletal Proteins ; Qb-SNARE Proteins ; Qc-SNARE Proteins ; SNARE Proteins ; Snap47 protein, mouse ; TRIM67 protein, mouse ; Tripartite Motif Proteins
    Language English
    Publishing date 2022-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.108743
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A pair of E3 ubiquitin ligases compete to regulate filopodial dynamics and axon guidance.

    Boyer, Nicholas P / McCormick, Laura E / Menon, Shalini / Urbina, Fabio L / Gupton, Stephanie L

    The Journal of cell biology

    2019  Volume 219, Issue 1

    Abstract: Appropriate axon guidance is necessary to form accurate neuronal connections. Axon guidance cues that stimulate cytoskeletal reorganization within the growth cone direct axon navigation. Filopodia at the growth cone periphery have long been considered ... ...

    Abstract Appropriate axon guidance is necessary to form accurate neuronal connections. Axon guidance cues that stimulate cytoskeletal reorganization within the growth cone direct axon navigation. Filopodia at the growth cone periphery have long been considered sensors for axon guidance cues, yet how they respond to extracellular cues remains ill defined. Our previous work found that the filopodial actin polymerase VASP and consequently filopodial stability are negatively regulated via nondegradative TRIM9-dependent ubiquitination. Appropriate VASP ubiquitination and deubiquitination are required for axon turning in response to the guidance cue netrin-1. Here we show that the TRIM9-related protein TRIM67 outcompetes TRIM9 for interacting with VASP and antagonizes TRIM9-dependent VASP ubiquitination. The surprising antagonistic roles of two closely related E3 ubiquitin ligases are required for netrin-1-dependent filopodial responses, axon turning and branching, and fiber tract formation. We suggest a novel model in which coordinated regulation of VASP ubiquitination by a pair of interfering ligases is a critical element of VASP dynamics, filopodial stability, and axon guidance.
    MeSH term(s) Animals ; Axon Guidance/physiology ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Cytoskeletal Proteins/physiology ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Nerve Tissue Proteins/physiology ; Netrin-1/genetics ; Netrin-1/metabolism ; Neurons/cytology ; Neurons/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Pseudopodia/physiology ; Tripartite Motif Proteins/physiology ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/physiology ; Ubiquitination
    Chemical Substances Cell Adhesion Molecules ; Cytoskeletal Proteins ; Microfilament Proteins ; Nerve Tissue Proteins ; Ntn1 protein, mouse ; Phosphoproteins ; TRIM67 protein, mouse ; Tripartite Motif Proteins ; Ubiquitin ; vasodilator-stimulated phosphoprotein ; Netrin-1 (158651-98-0) ; Trim9 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2019-11-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201902088
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ub I Zs.190: Show issues Location:
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  5. Article ; Online: Coordinated Regulation of CB1 Cannabinoid Receptors and Anandamide Metabolism Stabilizes Network Activity during Homeostatic Downscaling.

    Ye, Michael / Monroe, Sarah K / Gay, Sean M / Armstrong, Michael L / Youngstrom, Diane E / Urbina, Fabio L / Gupton, Stephanie L / Reisdorph, Nichole / Diering, Graham H

    eNeuro

    2022  Volume 9, Issue 6

    Abstract: Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the postsynaptic compartments to ... ...

    Abstract Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the postsynaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of presynaptic cannabinoid receptor type 1 (CB1). The eCB system is well situated to regulate neuronal network properties and coordinate presynaptic and postsynaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used Western blotting and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature cultured rat cortical neurons, and used multielectrode array (MEA) recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activity during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of
    MeSH term(s) Animals ; Rats ; Endocannabinoids/metabolism ; Receptors, Cannabinoid ; Arachidonic Acids/pharmacology ; Polyunsaturated Alkamides ; Glutamic Acid ; Receptor, Cannabinoid, CB1 ; Cannabinoid Receptor Modulators/pharmacology
    Chemical Substances anandamide (UR5G69TJKH) ; Endocannabinoids ; Receptors, Cannabinoid ; Arachidonic Acids ; Polyunsaturated Alkamides ; Glutamic Acid (3KX376GY7L) ; Receptor, Cannabinoid, CB1 ; Cannabinoid Receptor Modulators
    Language English
    Publishing date 2022-11-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2800598-3
    ISSN 2373-2822 ; 2373-2822
    ISSN (online) 2373-2822
    ISSN 2373-2822
    DOI 10.1523/ENEURO.0276-22.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Vinculin and metavinculin exhibit distinct effects on focal adhesion properties, cell migration, and mechanotransduction.

    Lee, Hyunna T / Sharek, Lisa / O'Brien, E Timothy / Urbina, Fabio L / Gupton, Stephanie L / Superfine, Richard / Burridge, Keith / Campbell, Sharon L

    PloS one

    2019  Volume 14, Issue 9, Page(s) e0221962

    Abstract: Vinculin (Vcn) is a ubiquitously expressed cytoskeletal protein that links transmembrane receptors to actin filaments, and plays a key role in regulating cell adhesion, motility, and force transmission. Metavinculin (MVcn) is a Vcn splice isoform that ... ...

    Abstract Vinculin (Vcn) is a ubiquitously expressed cytoskeletal protein that links transmembrane receptors to actin filaments, and plays a key role in regulating cell adhesion, motility, and force transmission. Metavinculin (MVcn) is a Vcn splice isoform that contains an additional exon encoding a 68-residue insert within the actin binding tail domain. MVcn is selectively expressed at sub-stoichiometic amounts relative to Vcn in smooth and cardiac muscle cells. Mutations in the MVcn insert are linked to various cardiomyopathies. In vitro analysis has previously shown that while both proteins can engage filamentous (F)-actin, only Vcn can promote F-actin bundling. Moreover, we and others have shown that MVcn can negatively regulate Vcn-mediated F-actin bundling in vitro. To investigate functional differences between MVcn and Vcn, we stably expressed either Vcn or MVcn in Vcn-null mouse embryonic fibroblasts. While both MVcn and Vcn were observed at FAs, MVcn-expressing cells had larger but fewer focal adhesions per cell compared to Vcn-expressing cells. MVcn-expressing cells migrated faster and exhibited greater persistence compared to Vcn-expressing cells, even though Vcn-containing FAs assembled and disassembled faster. Magnetic tweezer measurements on Vcn-expressing cells show a typical cell stiffening phenotype in response to externally applied force; however, this was absent in Vcn-null and MVcn-expressing cells. Our findings that MVcn expression leads to larger but fewer FAs per cell, in conjunction with the inability of MVcn to bundle F-actin in vitro and rescue the cell stiffening response, are consistent with our previous findings of actin bundling deficient Vcn variants, suggesting that deficient actin-bundling may account for some of the differences between Vcn and MVcn.
    MeSH term(s) Animals ; Cell Line ; Cell Movement ; Focal Adhesions ; Gene Expression Regulation ; Mechanotransduction, Cellular ; Mice ; Models, Molecular ; Protein Domains ; Vinculin/chemistry ; Vinculin/metabolism
    Chemical Substances metavinculin ; Vinculin (125361-02-6)
    Language English
    Publishing date 2019-09-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0221962
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching.

    Plooster, Melissa / Menon, Shalini / Winkle, Cortney C / Urbina, Fabio L / Monkiewicz, Caroline / Phend, Kristen D / Weinberg, Richard J / Gupton, Stephanie L

    Molecular biology of the cell

    2017  Volume 28, Issue 18, Page(s) 2374–2385

    Abstract: Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and ... ...

    Abstract Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and increases in exocytic vesicle fusion, yet how these occurrences are linked is unknown. Here we demonstrate that
    MeSH term(s) Animals ; Axons/enzymology ; Axons/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Membrane/metabolism ; DCC Receptor/metabolism ; Exocytosis/physiology ; Female ; Focal Adhesion Kinase 1/genetics ; Focal Adhesion Kinase 1/metabolism ; HEK293 Cells ; Humans ; Male ; Membrane Fusion ; Mice ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Netrin-1/genetics ; Netrin-1/metabolism ; Neurogenesis/physiology ; Neurons/cytology ; Neurons/enzymology ; Neurons/metabolism ; Phosphorylation ; Pregnancy ; Signal Transduction ; Tripartite Motif Proteins/genetics ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; src-Family Kinases/metabolism
    Chemical Substances Carrier Proteins ; DCC Receptor ; DCC protein, human ; Dcc protein, mouse ; Nerve Tissue Proteins ; Ntn1 protein, mouse ; Tripartite Motif Proteins ; Netrin-1 (158651-98-0) ; TRIM9 protein, human (EC 2.3.2.27) ; Trim9 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; Ptk2 protein, mouse (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2017-07-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E16-08-0594
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 410: Show issues

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