Crucial polarity regulators in axon specification

2012 ◽  
Vol 53 ◽  
pp. 55-68 ◽  
Author(s):  
Giovanna Lalli
Keyword(s):  
Nervous System ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Membrane Traffic ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Microtubule Cytoskeleton ◽  
Morphological Asymmetry ◽  
Neuronal Polarization

Cell polarization is critical for the correct functioning of many cell types, creating functional and morphological asymmetry in response to intrinsic and extrinsic cues. Neurons are a classical example of polarized cells, as they usually extend one long axon and short branched dendrites. The formation of such distinct cellular compartments (also known as neuronal polarization) ensures the proper development and physiology of the nervous system and is controlled by a complex set of signalling pathways able to integrate multiple polarity cues. Because polarization is at the basis of neuronal development, investigating the mechanisms responsible for this process is fundamental not only to understand how the nervous system develops, but also to devise therapeutic strategies for neuroregeneration. The last two decades have seen remarkable progress in understanding the molecular mechanisms responsible for mammalian neuronal polarization, primarily using cultures of rodent hippocampal neurons. More recent efforts have started to explore the role of such mechanisms in vivo. It has become clear that neuronal polarization relies on signalling networks and feedback mechanisms co-ordinating the actin and microtubule cytoskeleton and membrane traffic. The present chapter will highlight the role of key molecules involved in neuronal polarization, such as regulators of the actin/microtubule cytoskeleton and membrane traffic, polarity complexes and small GTPases.

Cell motility: can Rho GTPases and microtubules point the way?

2001 ◽  
Vol 114 (21) ◽  
pp. 3795-3803 ◽  
Author(s):  
Torsten Wittmann ◽  
Clare M. Waterman-Storer
Keyword(s):  
Actin Cytoskeleton ◽  
Cell Motility ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Cell Types ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Microtubule Cytoskeleton ◽  
Filament Bundles

Migrating cells display a characteristic polarization of the actin cytoskeleton. Actin filaments polymerise in the protruding front of the cell whereas actin filament bundles contract in the cell body, which results in retraction of the cell’s rear. The dynamic organization of the actin cytoskeleton provides the force for cell motility and is regulated by small GTPases of the Rho family, in particular Rac1, RhoA and Cdc42. Although the microtubule cytoskeleton is also polarized in a migrating cell, and microtubules are essential for the directed migration of many cell types, their role in cell motility is not well understood at a molecular level. Here, we discuss the potential molecular mechanisms for interplay of microtubules, actin and Rho GTPase signalling in cell polarization and motility. Recent evidence suggests that microtubules locally modulate the activity of Rho GTPases and, conversely, Rho GTPases might be responsible for the initial polarization of the microtubule cytoskeleton. Thus, microtubules might be part of a positive feedback mechanism that maintains the stable polarization of a directionally migrating cell.

scholarly journals Deletion of the Actin-Associated Tropomyosin Tpm3 Leads to Reduced Cell Complexity in Cultured Hippocampal Neurons—New Insights into the Role of the C-Terminal Region of Tpm3.1

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 715
Author(s):  
Tamara Tomanić ◽  
Claire Martin ◽  
Holly Stefen ◽  
Esmeralda Parić ◽  
Peter Gunning ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Growth Cones ◽  
Amino Acid Residues ◽  
Terminal Amino Acid ◽  
C Terminus ◽  
Primary Mouse ◽  
Terminal Amino

Tropomyosins (Tpms) have been described as master regulators of actin, with Tpm3 products shown to be involved in early developmental processes, and the Tpm3 isoform Tpm3.1 controlling changes in the size of neuronal growth cones and neurite growth. Here, we used primary mouse hippocampal neurons of C57/Bl6 wild type and Bl6Tpm3flox transgenic mice to carry out morphometric analyses in response to the absence of Tpm3 products, as well as to investigate the effect of C-terminal truncation on the ability of Tpm3.1 to modulate neuronal morphogenesis. We found that the knock-out of Tpm3 leads to decreased neurite length and complexity, and that the deletion of two amino acid residues at the C-terminus of Tpm3.1 leads to more detrimental changes in neurite morphology than the deletion of six amino acid residues. We also found that Tpm3.1 that lacks the 6 C-terminal amino acid residues does not associate with stress fibres, does not segregate to the tips of neurites, and does not impact the amount of the filamentous actin pool at the axonal growth cones, as opposed to Tpm3.1, which lacks the two C-terminal amino acid residues. Our study provides further insight into the role of both Tpm3 products and the C-terminus of Tpm3.1, and it forms the basis for future studies that aim to identify the molecular mechanisms underlying Tpm3.1 targeting to different subcellular compartments.

Сellular and Molecular Mechanisms of Proinflammatory Monocytes Participation in the Pathogenesis of Mental Disorders. Part 3

Psychiatry ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 125-134
Author(s):  
E. F. Vasilyeva ◽  
O. S. Brusov
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mental Disorders ◽  
Molecular Mechanisms ◽  
Microglial Cells ◽  
Inflammatory Reactions ◽  
Mental Diseases ◽  
The Central Nervous System ◽  
The Brain

Background: at present, the important role of the monocyte-macrophage link of immunity in the pathogenesis of mental diseases has been determined. In the first and second parts of our review, the cellular and molecular mechanisms of activation of monocytes/macrophages, which secreting proinflammatory CD16 receptors, cytokines, chemokines and receptors to them, in the development of systemic immune inflammation in the pathogenesis of somatic diseases and mental disorders, including schizophrenia, bipolar affective disorder (BAD) and depression were analyzed. The association of high levels of proinflammatory activity of monocytes/macrophages in patients with mental disorders with somatic comorbidity, including immune system diseases, is shown. It is known that proinflammatory monocytes of peripheral blood, as a result of violation of the integrity of the hematoencephalic barrier can migrate to the central nervous system and activate the resident brain cells — microglia, causing its activation. Activation of microglia can lead to the development of neuroinammation and neurodegenerative processes in the brain and, as a result, to cognitive disorders. The aim of review: to analyze the results of the main scientific studies concerning the role of cellular and molecular mechanisms of peripheral blood monocytes interaction with microglial cells and platelets in the development of neuroinflammation in the pathogenesis of mental disorders, including Alzheimer’s disease (AD). Material and methods: keywords “mental disorders, AD, proinflammatory monocytes, microglia, neuroinflammation, cytokines, chemokines, cell adhesion molecules, platelets, microvesicles” were used to search for articles of domestic and foreign authors published over the past 30 years in the databases PubMed, eLibrary, Science Direct and EMBASE. Conclusion: this review analyzes the results of studies which show that monocytes/macrophages and microglia have similar gene expression profiles in schizophrenia, BAD, depression, and AD and also perform similar functions: phagocytosis and inflammatory responses. Monocytes recruited to the central nervous system stimulate the increased production of proinflammatory cytokines IL-1, IL-6, tumor necrosis factor alpha (TNF-α), chemokines, for example, MCP-1 (Monocyte chemotactic protein-1) by microglial cells. This promotes the recruitment of microglial cells to the sites of neuronal damage, and also enhances the formation of the brain protein beta-amyloid (Aβ). The results of modern studies are presented, indicating that platelets are involved in systemic inflammatory reactions, where they interact with monocytes to form monocyte-platelet aggregates (MTA), which induce the activation of monocytes with a pro inflammatory phenotype. In the last decade, it has been established that activated platelets and other cells of the immune system, including monocytes, detached microvesicles (MV) from the membrane. It has been shown that MV are involved as messengers in the transport of biologically active lipids, cytokines, complement, and other molecules that can cause exacerbation of systemic inflammatory reactions. The presented review allows us to expand our knowledge about the cellular and molecular aspects of the interaction of monocytes/macrophages with microglial cells and platelets in the development of neuroinflammation and cognitive decline in the pathogenesis of mental diseases and in AD, and also helps in the search for specific biomarkers of the clinical severity of mental disorder in patients and the prospects for their response to treatment.

scholarly journals Gut–Brain Axis and Neurodegeneration: State-of-the-Art of Meta-Omics Sciences for Microbiota Characterization

2020 ◽  
Vol 21 (11) ◽  
pp. 4045 ◽  
Author(s):  
Bruno Tilocca ◽  
Luisa Pieroni ◽  
Alessio Soggiu ◽  
Domenico Britti ◽  
Luigi Bonizzi ◽  
...  
Keyword(s):  
Nervous System ◽  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
State Of The Art ◽  
Integrated Approach ◽  
Microbial Genomes ◽  
Physiological Processes ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in a finely tuned network of interconnections with the host, orchestrating a wide variety of physiological processes. These includes the bi-directional crosstalk between the central nervous system, the enteric nervous system, and the gastrointestinal tract (i.e., gut–brain axis). The increasing accumulation of evidence suggest a pivotal role of the composition and activity of the gut microbiota in neurodegeneration. In the present review we aim to provide an overview of the state-of-the-art of meta-omics sciences including metagenomics for the study of microbial genomes and taxa strains, metatranscriptomics for gene expression, metaproteomics and metabolomics to identify and/or quantify microbial proteins and metabolites, respectively. The potential and limitations of each discipline were highlighted, as well as the advantages of an integrated approach (multi-omics) to predict microbial functions and molecular mechanisms related to human diseases. Particular emphasis is given to the latest results obtained with these approaches in an attempt to elucidate the link between the gut microbiota and the most common neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

The V-ATPase a2-subunit as a putative endosomal pH-sensor

2007 ◽  
Vol 35 (5) ◽  
pp. 1092-1099 ◽  
Author(s):  
V. Marshansky
Keyword(s):  
Crucial Role ◽  
Molecular Mechanisms ◽  
Ph Sensor ◽  
Small Gtpases ◽  
Ph Sensitive ◽  
Ph Sensing ◽  
Degradative Pathway ◽  
Histidine Residues ◽  
Endosomal Acidification

V-ATPase (vesicular H+-ATPase)-driven intravesicular acidification is crucial for vesicular trafficking. Defects in vesicular acidification and trafficking have recently been recognized as essential determinants of various human diseases. An important role of endosomal acidification in receptor–ligand dissociation and in activation of lysosomal hydrolytic enzymes is well established. However, the molecular mechanisms by which luminal pH information is transmitted to the cytosolic small GTPases that control trafficking events such as budding, coat formation and fusion are unknown. Here, we discuss our recent discovery that endosomal V-ATPase is a pH-sensor regulating the degradative pathway. According to our model, V-ATPase is responsible for: (i) the generation of a pH gradient between vesicular membranes; (ii) sensing of intravesicular pH; and (iii) transmitting this information to the cytosolic side of the membrane. We also propose the hypothetical molecular mechanism involved in function of the V-ATPase a2-subunit as a putative pH-sensor. Based on extensive experimental evidence on the crucial role of histidine residues in the function of PSPs (pH-sensing proteins) in eukaryotic cells, we hypothesize that pH-sensitive histidine residues within the intra-endosomal loops and/or C-terminal luminal tail of the a2-subunit could also be involved in the pH-sensing function of V-ATPase. However, in order to identify putative pH-sensitive histidine residues and to test this hypothesis, it is absolutely essential that we increase our understanding of the folding and transmembrane topology of the a-subunit isoforms of V-ATPase. Thus the crucial role of intra-endosomal histidine residues in pH-dependent conformational changes of the V-ATPase a2-isoform, its interaction with cytosolic small GTPases and ultimately in its acidification-dependent regulation of the endosomal/lysosomal protein degradative pathway remain to be determined.

scholarly journals Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

2015 ◽  
Vol 112 (51) ◽  
pp. 15755-15760 ◽  
Author(s):  
Miyeon Choi ◽  
Seung Hoon Lee ◽  
Sung Eun Wang ◽  
Seung Yeon Ko ◽  
Mihee Song ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Nuclear Export ◽  
Hippocampal Neurons ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Calmodulin Kinase ◽  
Defective Mutant ◽  
Antidepressant Effects

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.

Glial differentiation and the Gcm pathway

2007 ◽  
Vol 3 (1) ◽  
pp. 5-16 ◽  
Author(s):  
Laurent Soustelle ◽  
Angela Giangrande
Keyword(s):  
Developmental Biology ◽  
Nervous System ◽  
Neural Development ◽  
Molecular Mechanisms ◽  
Stem Cell Differentiation ◽  
Molecular Pathways ◽  
Glial Differentiation ◽  
Cell Diversity ◽  
Necessary And Sufficient

AbstractOne of the most challenging issues in developmental biology is to understand how cell diversity is generated. The Drosophila nervous system provides a model of choice for unraveling this process. First, many neural stem cells and lineages have been identified. Second, major molecular pathways involved in neural development and associated mutations have been characterized extensively in recent years. In this review, we focus on the cellular and molecular mechanisms underlying the generation of glia. This cell population relies on the expression of gcm fate determinant, which is necessary and sufficient to induce glial differentiation. We also discuss the recently identified role of gcm genes in Drosophila melanogaster and vertebrate neurogenesis. Finally, we will consider the Gcm pathway in the context of neural stem cell differentiation.

scholarly journals The Role of Astrocytes in the Central Nervous System Focused on BK Channel and Heme Oxygenase Metabolites: A Review

Antioxidants ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 121 ◽  
Author(s):  
Yonghee Kim ◽  
Jinhong Park ◽  
Yoon Kyung Choi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Bk Channel ◽  
Cns Injury ◽  
Antioxidant Agents ◽  
The Central Nervous System

Astrocytes outnumber neurons in the human brain, and they play a key role in numerous functions within the central nervous system (CNS), including glutamate, ion (i.e., Ca2+, K+) and water homeostasis, defense against oxidative/nitrosative stress, energy storage, mitochondria biogenesis, scar formation, tissue repair via angiogenesis and neurogenesis, and synapse modulation. After CNS injury, astrocytes communicate with surrounding neuronal and vascular systems, leading to the clearance of disease-specific protein aggregates, such as β-amyloid, and α-synuclein. The astrocytic big conductance K+ (BK) channel plays a role in these processes. Recently, potential therapeutic agents that target astrocytes have been tested for their potential to repair the brain. In this review, we discuss the role of the BK channel and antioxidant agents such as heme oxygenase metabolites following CNS injury. A better understanding of the cellular and molecular mechanisms of astrocytes’ functions in the healthy and diseased brains will greatly contribute to the development of therapeutic approaches following CNS injury, such as Alzheimer’s disease, Parkinson’s disease, and stroke.

scholarly journals Squeezing out in a “tug of war”: The role of myosin in neural stem cell delamination

2017 ◽  
Vol 216 (5) ◽  
pp. 1215-1218
Author(s):  
Clara Sidor ◽  
Katja Röper
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Drosophila Melanogaster ◽  
Stem Cell ◽  
Spatial Resolution ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Apical Constriction ◽  
Temporal And Spatial

Neural stem cells or neuroblasts in the Drosophila melanogaster embryo delaminate as single cells from the embryonic epidermis to give rise to the nervous system. Using this accessible system to examine the molecular mechanisms of cell ingression at a high temporal and spatial resolution, in this issue, Simões et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608038) reveal that myosin-driven anisotropic junction loss and apical constriction are the main drivers of this process.

scholarly journals The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications

2019 ◽  
Vol 20 (12) ◽  
pp. 3022 ◽  
Author(s):  
Jessica Maiuolo ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
Saverio Nucera ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nervous System ◽  
Erectile Dysfunction ◽  
Endothelial Dysfunction ◽  
Peripheral Nerves ◽  
Molecular Mechanisms ◽  
Nerve Tissue ◽  
Nerve Degeneration ◽  
Peripheral Nerve Damage

The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve.

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