scholarly journals Netrin instructs synaptic vesicle clustering through Rac GTPase, MIG-10, and the actin cytoskeleton

2012 ◽  
Vol 197 (1) ◽  
pp. 75-88 ◽  
Author(s):  
Andrea K.H. Stavoe ◽  
Daniel A. Colón-Ramos
Keyword(s):  
Cell Migration ◽  
Subcellular Localization ◽  
Actin Cytoskeleton ◽  
Axon Guidance ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Rac Gtpase ◽  
Signaling Modules

Netrin is a chemotrophic factor known to regulate a number of neurodevelopmental processes, including cell migration, axon guidance, and synaptogenesis. Although the role of Netrin in synaptogenesis is conserved throughout evolution, the mechanisms by which it instructs synapse assembly are not understood. Here we identify a mechanism by which the Netrin receptor UNC-40/DCC instructs synaptic vesicle clustering in vivo. UNC-40 localized to presynaptic regions in response to Netrin. We show that UNC-40 interacted with CED-5/DOCK180 and instructed CED-5 presynaptic localization. CED-5 in turn signaled through CED-10/Rac1 and MIG-10/Lamellipodin to organize the actin cytoskeleton in presynaptic regions. Localization of this signaling pathway to presynaptic regions was necessary for synaptic vesicle clustering during synapse assembly but not for the subcellular localization of active zone proteins. Thus, vesicle clustering and localization of active zone proteins are instructed by separate pathways downstream of Netrin. Our data indicate that signaling modules known to organize the actin cytoskeleton during guidance can be co-opted to instruct synaptic vesicle clustering.

scholarly journals Role of Berry Anthocyanins and Phenolic Acids on Cell Migration and Angiogenesis: An Updated Overview

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1075 ◽  
Author(s):  
Panagiotis Tsakiroglou ◽  
Natalie E. VandenAkker ◽  
Cristian Del Bo’ ◽  
Patrizia Riso ◽  
Dorothy Klimis-Zacas
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Phenolic Acids ◽  
Rho Gtpase ◽  
Small Gtpases ◽  
Endothelial Cell Migration ◽  
Berry Extracts

Cell migration is a critical process that is highly involved with normal and pathological conditions such as angiogenesis and wound healing. Important members of the RHO GTPase family are capable of controlling cytoskeleton conformation and altering motility characteristics of cells. There is a well-known relationship between small GTPases and the PI3K/AKT pathway. Endothelial cell migration can lead to angiogenesis, which is highly linked to wound healing processes. Phenolics, flavonoids, and anthocyanins are major groups of phytochemicals and are abundant in many natural products. Their antioxidant, antimicrobial, anti-inflammatory, antidiabetic, angiogenenic, neuroprotective, hepatoprotective, and cardioprotective properties have been extensively documented. This comprehensive review focuses on the in vitro and in vivo role of berry extracts and single anthocyanin and phenolic acid compounds on cell migration and angiogenesis. We aim to summarize the most recent published studies focusing on the experimental model, type of berry extract, source, dose/concentration and overall effect(s) of berry extracts, anthocyanins, and phenolic acids on the above processes.

scholarly journals Role of cell migration in the pathogenesis of rheumatoid arthritis: in vivo studies in SCID mice transplanted with human synovial membrane

Reumatismo ◽  
2011 ◽  
Vol 54 (2) ◽  
Author(s):  
F. Ingegnoli ◽  
M. Blades ◽  
A. Manzo ◽  
S. Wahid ◽  
M. Perretti ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Synovial Membrane ◽  
Scid Mice ◽  
In Vivo Studies

scholarly journals Shared and Unique Roles of Cap23 and Gap43 in Actin Regulation, Neurite Outgrowth, and Anatomical Plasticity

2000 ◽  
Vol 149 (7) ◽  
pp. 1443-1454 ◽  
Author(s):  
Dunja Frey ◽  
Thorsten Laux ◽  
Lan Xu ◽  
Corinna Schneider ◽  
Pico Caroni
Keyword(s):  
Actin Cytoskeleton ◽  
Neurite Outgrowth ◽  
Critical Role ◽  
Brain Structures ◽  
Calmodulin Binding ◽  
Essentially Normal ◽  
Anatomical Plasticity ◽  
Nerve Sprouting

CAP23 is a major cortical cytoskeleton–associated and calmodulin binding protein that is widely and abundantly expressed during development, maintained in selected brain structures in the adult, and reinduced during nerve regeneration. Overexpression of CAP23 in adult neurons of transgenic mice promotes nerve sprouting, but the role of this protein in process outgrowth was not clear. Here, we show that CAP23 is functionally related to GAP43, and plays a critical role to regulate nerve sprouting and the actin cytoskeleton. Knockout mice lacking CAP23 exhibited a pronounced and complex phenotype, including a defect to produce stimulus-induced nerve sprouting at the adult neuromuscular junction. This sprouting deficit was rescued by transgenic overexpression of either CAP23 or GAP43 in adult motoneurons. Knockin mice expressing GAP43 instead of CAP23 were essentially normal, indicating that, although these proteins do not share homologous sequences, GAP43 can functionally substitute for CAP23 in vivo. Cultured sensory neurons lacking CAP23 exhibited striking alterations in neurite outgrowth that were phenocopied by low doses of cytochalasin D. A detailed analysis of such cultures revealed common and unique functions of CAP23 and GAP43 on the actin cytoskeleton and neurite outgrowth. The results provide compelling experimental evidence for the notion that CAP23 and GAP43 are functionally related intrinsic determinants of anatomical plasticity, and suggest that these proteins function by locally promoting subplasmalemmal actin cytoskeleton accumulation.

Force-dependent vinculin binding to talin in live cells: a crucial step in anchoring the actin cytoskeleton to focal adhesions

2014 ◽  
Vol 306 (6) ◽  
pp. C607-C620 ◽  
Author(s):  
Hiroaki Hirata ◽  
Hitoshi Tatsumi ◽  
Chwee Teck Lim ◽  
Masahiro Sokabe
Keyword(s):  
Actin Cytoskeleton ◽  
Focal Adhesions ◽  
Living Cells ◽  
Live Cells ◽  
Mechanical Forces ◽  
Actin Network ◽  
Crucial Step

Mechanical forces play a pivotal role in the regulation of focal adhesions (FAs) where the actin cytoskeleton is anchored to the extracellular matrix through integrin and a variety of linker proteins including talin and vinculin. The localization of vinculin at FAs depends on mechanical forces. While in vitro studies have demonstrated the force-induced increase in vinculin binding to talin, it remains unclear whether such a mechanism exists at FAs in vivo. In this study, using fibroblasts cultured on elastic silicone substrata, we have examined the role of forces in modulating talin-vinculin binding at FAs. Stretching the substrata caused vinculin accumulation at talin-containing FAs, and this accumulation was abrogated by expressing the talin-binding domain of vinculin (domain D1, which inhibits endogenous vinculin from binding to talin). These results indicate that mechanical forces loaded to FAs facilitate vinculin binding to talin at FAs. In cell-protruding regions, the actin network moved backward over talin-containing FAs in domain D1-expressing cells while it was anchored to FAs in control cells, suggesting that the force-dependent vinculin binding to talin is crucial for anchoring the actin cytoskeleton to FAs in living cells.

scholarly journals Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of Glioblastoma

2020 ◽  
Author(s):  
Montserrat Lara-Velazquez ◽  
Natanael Zarco ◽  
Anna Carrano ◽  
Jordan Phillipps ◽  
Emily S Norton ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Migration ◽  
Brain Tumor ◽  
Primary Cultures ◽  
Cellular Migration ◽  
Tumor Initiating Cells ◽  
The Impact

Abstract Background Glioblastomas (GBMs) are the most common primary brains tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for reasons that remain unknown. One potential explanation is the proximity of these tumors to the cerebrospinal fluid (CSF) and its contained chemical cues that can regulate cellular migration and differentiation. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods We utilized patient-derived CSF and primary cultures of GBM brain tumor initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using TCGA database. SERPINA3 expression changes were evaluated at both the mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell behavior were evaluated by transwell assay (for cell migration), and alamar blue and Ki67 (for viability and proliferation respectively). Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results GBM CSF induced a significant increase in BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. Silencing of SERPINA3 induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 overexpression increased cell migration. In vivo, mice orthotopically-injected with SERPINA3 KD BTICs showed increased survival. Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

scholarly journals ARHGAP25, a novel Rac GTPase-activating protein, regulates phagocytosis in human neutrophilic granulocytes

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 573-582 ◽  
Author(s):  
Roland Csépányi-Kömi ◽  
Gábor Sirokmány ◽  
Miklós Geiszt ◽  
Erzsébet Ligeti
Keyword(s):  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
Active Form ◽  
Cell Types ◽  
Small Gtpases ◽  
Negative Regulator ◽  
Phagocytic Cells ◽  
Rac Gtpase

Members of the Rac/Rho family of small GTPases play an essential role in phagocytic cells in organization of the actin cytoskeleton and production of toxic oxygen compounds. GTPase-activating proteins (GAPs) decrease the amount of the GTP-bound active form of small GTPases, and contribute to the control of biologic signals. The number of potential Rac/RhoGAPs largely exceeds the number of Rac/Rho GTPases and the expression profile, and their specific role in different cell types is largely unknown. In this study, we report for the first time the properties of full-length ARHGAP25 protein, and show that it is specifically expressed in hematopoietic cells, and acts as a RacGAP both in vitro and in vivo. By silencing and overexpressing the protein in neutrophil model cell lines (PLB-985 and CosPhoxFcγR, respectively) and in primary macrophages, we demonstrate that ARHGAP25 is a negative regulator of phagocytosis acting probably via modulation of the actin cytoskeleton.

scholarly journals Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Veronica Cloud ◽  
Ada Thapa ◽  
Pedro Morales-Sosa ◽  
Tayla M Miller ◽  
Sara A Miller ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Actin Cytoskeleton ◽  
Spinocerebellar Ataxia Type ◽  
Amino Terminus ◽  
Heterozygous Mutation ◽  
Polyglutamine Expansion ◽  
Cytoskeleton Organization ◽  
Protein Levels ◽  
Spinocerebellar Ataxia Type 7

Atxn7, a subunit of SAGA chromatin remodeling complex, is subject to polyglutamine expansion at the amino terminus, causing spinocerebellar ataxia type 7 (SCA7), a progressive retinal and neurodegenerative disease. Within SAGA, the Atxn7 amino terminus anchors Non-stop, a deubiquitinase, to the complex. To understand the scope of Atxn7-dependent regulation of Non-stop, substrates of the deubiquitinase were sought. This revealed Non-stop, dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC), which control actin cytoskeleton assembly. There, Non-stop countered polyubiquitination and proteasomal degradation of WRC subunit SCAR. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop augmentation increased protein levels, and directed subcellular localization, of SCAR, decreasing cell area and number of protrusions. In vivo, heterozygous mutation of SCAR did not significantly rescue knockdown of Atxn7, but heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR.

scholarly journals Flavin Monooxygenases Regulate C. elegans Axon Guidance and Growth Cone Protrusion with UNC-6/Netrin signaling and Rac GTPases

2017 ◽  
Author(s):  
Mahekta Gujar ◽  
Aubrie M. Stricker ◽  
Erik A. Lundquist
Keyword(s):  
Axon Guidance ◽  
Growth Cone ◽  
Molecular Mechanisms ◽  
Direct Oxidation ◽  
Rac Gtpase ◽  
C Elegans ◽  
Growth Cone Collapse ◽  
Rac Gtpases ◽  
Inhibition Of Growth

AbstractThe guidance cue UNC-6/Netrin regulates both attractive and repulsive axon guidance. Our previous work showed that in C. elegans, the attractive UNC-6/Netrin receptor UNC-40/DCC stimulates growth cone protrusion, and that the repulsive receptor, an UNC-5/UNC-40 heterodimer, inhibits growth cone protrusion. We have also shown that inhibition of growth cone protrusion downstream of the UNC-5/UNC-40 repulsive receptor involves Rac GTPases, the Rac GTP exchange factor UNC-73/Trio, and the cytoskeletal regulator UNC-33/CRMP, which mediates Semaphorin-induced growth cone collapse in other systems. The multidomain flavoprotein monooxygenase (FMO) MICAL also mediates growth cone collapse in response to Semaphorin by directly oxidizing F-actin, resulting in depolymerization. The C. elegans genome does not encode a multidomain MICAL-like molecule, but does encode five flavin monooxygenases (FMO-1, -2, -3, -4, and 5) and another molecule, EHBP-1, similar to the non-FMO portion of MICAL.Here we show that FMO-1, FMO-4, FMO-5, and EHBP-1 may play a role in UNC-6/Netrin directed repulsive guidance mediated through UNC-40 and UNC-5 receptors. Mutations in fmo-1, fmo-4, fmo-5, and ehbp-1 showed VD/DD axon guidance and branching defects, and variably enhanced unc-40 and unc-5 VD/DD guidance defects. Developing growth cones in vivo of fmo-1, fmo-4, fmo-5, and ehbp-1 mutants displayed excessive filopodial protrusion, and transgenic expression of FMO-5 inhibited growth cone protrusion. Mutations suppressed growth cone inhibition caused by activated UNC-40 and UNC-5 signaling, and activated Rac GTPase CED-10 and MIG-2, suggesting that these molecules are required downstream of UNC-6/Netrin receptors and Rac GTPases. From these studies, we conclude that FMO-1, FMO-4, FMO-5, and EHBP-1 represent new players downstream of UNC-6/Netrin receptors and Rac GTPases that inhibit growth cone filopodial protrusion in repulsive axon guidance.Author SummaryMolecular mechanisms of axon repulsion mediated by UNC-6/Netrin are not well understood. Inhibition of growth cone lamellipodial and filopodial protrusion is critical to repulsive axon guidance. Previous work identified a novel pathway involving Rac GTPases and the cytoskeletal interacting molecule UNC-33/CRMP required for UNC-6/Netrin-mediated inhibition of growth cone protrusion. In other systems, CRMP mediates growth cone collapse in response to semaphorin. Here we demonstrate a novel role of flavoprotein monooxygenases (FMOs) in repulsive axon guidance and inhibition of growth cone protrusion downstream of UNC-6/Netrin signaling and Rac GTPases. In Drosophila and vertebrates, the multidomain MICAL FMO mediates semaphorin-dependent growth cone collapse by direct oxidation and depolymerization of F-actin. The C. elegans genome does not encode a multidomain MICAL-like molecule, and we speculate that the C. elegans FMOs might have an equivalent role downstream of UNC-6/Netrin signaling. Indeed, we show that EHBP-1, similar to the non-FMO portion of MICAL, also controls repulsive axon guidance and growth cone inhibition, suggesting that in C. elegans, the functions of the multidomain MICAL molecule might be distributed across different molecules. In sum, we show conservation of function of molecules involved in semaphorin growth cone collapse with inhibition of growth cone protrusion downstream of UNC-6/Netrin signaling.

scholarly journals Actin dynamics regulation by TTC7A/PI4KIIIα axis limits DNA damage and cell death during leukocyte migration

2021 ◽  
Author(s):  
Tania Gajardo ◽  
Marie Lo ◽  
Mathilde Bernard ◽  
Claire Leveau ◽  
Marie-Therese El-Daher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Leukocyte Migration ◽  
Actin Dynamics ◽  
Immune Homeostasis ◽  
Cellular Functions ◽  
The Impact

The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cell processes, including cell migration. Mutations in the TTC7A gene have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. Although several cellular functions have been associated with TTC7A, the role of the protein in the maintenance of the immune homeostasis is still poorly understood. Here we leverage microfabricated devices to investigate the impact of TTC7A deficiency in leukocytes migration at the single cell level. We show that TTC7A-deficient leukocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositides signaling, leading to the downregulation of the PI3K/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamic. This resulted in impaired cell motility, accumulation of DNA damage and increased cell death during chemotaxis in dense 3D gels. Our results highlight a novel role of TTC7A as a critical regulator of leukocyte migration. Impairment of this cellular function is likely to contribute to pathophysiology underlying progressive immunodeficiency in patients.

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