Journal articles: 'POLARIDAD NEURONAL'

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Namba, Takashi, Yasuhiro Funahashi, Shinichi Nakamuta, Chundi Xu, Tetsuya Takano, and Kozo Kaibuchi. "Extracellular and Intracellular Signaling for Neuronal Polarity." Physiological Reviews 95, no. 3 (July 2015): 995–1024. http://dx.doi.org/10.1152/physrev.00025.2014.

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Neurons are one of the highly polarized cells in the body. One of the fundamental issues in neuroscience is how neurons establish their polarity; therefore, this issue fascinates many scientists. Cultured neurons are useful tools for analyzing the mechanisms of neuronal polarization, and indeed, most of the molecules important in their polarization were identified using culture systems. However, we now know that the process of neuronal polarization in vivo differs in some respects from that in cultured neurons. One of the major differences is their surrounding microenvironment; neurons in vivo can be influenced by extrinsic factors from the microenvironment. Therefore, a major question remains: How are neurons polarized in vivo? Here, we begin by reviewing the process of neuronal polarization in culture conditions and in vivo. We also survey the molecular mechanisms underlying neuronal polarization. Finally, we introduce the theoretical basis of neuronal polarization and the possible involvement of neuronal polarity in disease and traumatic brain injury.

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Hammond, Jennetta W., Chun-Fang Huang, Stefanie Kaech, Catherine Jacobson, Gary Banker, and Kristen J. Verhey. "Posttranslational Modifications of Tubulin and the Polarized Transport of Kinesin-1 in Neurons." Molecular Biology of the Cell 21, no. 4 (February 15, 2010): 572–83. http://dx.doi.org/10.1091/mbc.e09-01-0044.

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Polarized transport by microtubule-based motors is critical for neuronal development and function. Selective translocation of the Kinesin-1 motor domain is the earliest known marker of axonal identity, occurring before morphological differentiation. Thus, Kinesin-1–mediated transport may contribute to axonal specification. We tested whether posttranslational modifications of tubulin influence the ability of Kinesin-1 motors to distinguish microtubule tracks during neuronal development. We detected no difference in microtubule stability between axons and minor neurites in polarized stage 3 hippocampal neurons. In contrast, microtubule modifications were enriched in a subset of neurites in unpolarized stage 2 cells and the developing axon in polarized stage 3 cells. This enrichment correlated with the selective accumulation of constitutively active Kinesin-1 motors. Increasing tubulin acetylation, without altering the levels of other tubulin modifications, did not alter the selectivity of Kinesin-1 accumulation in polarized cells. However, globally enhancing tubulin acetylation, detyrosination, and polyglutamylation by Taxol treatment or inhibition of glycogen synthase kinase 3β decreased the selectivity of Kinesin-1 translocation and led to the formation of multiple axons. Although microtubule acetylation enhances the motility of Kinesin-1, the preferential translocation of Kinesin-1 on axonal microtubules in polarized neuronal cells is not determined by acetylation alone but is probably specified by a combination of tubulin modifications.

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Yuan, Xiao-bing, Zheng-hong Zhang, and Jian Jiang. "Traction of neuronal migration by polarized adhesion." Neuroscience Research 71 (September 2011): e28. http://dx.doi.org/10.1016/j.neures.2011.07.119.

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Krapp, Holger G. "Sensory Integration: Neuronal Filters for Polarized Light Patterns." Current Biology 24, no. 18 (September 2014): R840—R841. http://dx.doi.org/10.1016/j.cub.2014.08.020.

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Tas, Roderick P., Anaël Chazeau, Bas M. C. Cloin, Maaike L. A. Lambers, Casper C. Hoogenraad, and Lukas C. Kapitein. "Differentiation between Oppositely Oriented Microtubules Controls Polarized Neuronal Transport." Neuron 96, no. 6 (December 2017): 1264–71. http://dx.doi.org/10.1016/j.neuron.2017.11.018.

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Witte, Harald, Dorothee Neukirchen, and Frank Bradke. "Microtubule stabilization specifies initial neuronal polarization." Journal of Cell Biology 180, no. 3 (February 11, 2008): 619–32. http://dx.doi.org/10.1083/jcb.200707042.

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Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polarized cells. Loss of polarity or formation of multiple axons after manipulation of neuronal polarity regulators, synapses of amphids defective (SAD) kinases, and glycogen synthase kinase-3β correlates with characteristic changes in microtubule turnover. Consistently, changing the microtubule dynamics is sufficient to alter neuronal polarization. Application of low doses of the microtubule-destabilizing drug nocodazole selectively reduces the formation of future dendrites. Conversely, low doses of the microtubule-stabilizing drug taxol shift polymerizing microtubules from neurite shafts to process tips and lead to the formation of multiple axons. Finally, local stabilization of microtubules using a photoactivatable analogue of taxol induces axon formation from the activated area. Thus, local microtubule stabilization in one neurite is a physiological signal specifying neuronal polarization.

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Zhou, Zhengrong, Honglin Xu, Yuejia Li, Mengge Yang, Rui Zhang, Aki Shiraishi, Hiroshi Kiyonari, et al. "CAMSAP1 breaks the homeostatic microtubule network to instruct neuronal polarity." Proceedings of the National Academy of Sciences 117, no. 36 (August 24, 2020): 22193–203. http://dx.doi.org/10.1073/pnas.1913177117.

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The establishment of axon/dendrite polarity is fundamental for neurons to integrate into functional circuits, and this process is critically dependent on microtubules (MTs). In the early stages of the establishment process, MTs in axons change dramatically with the morphological building of neurons; however, how the MT network changes are triggered is unclear. Here we show that CAMSAP1 plays a decisive role in the neuronal axon identification process by regulating the number of MTs. Neurons lacking CAMSAP1 form a multiple axon phenotype in vitro, while the multipolar-bipolar transition and radial migration are blocked in vivo. We demonstrate that the polarity regulator MARK2 kinase phosphorylates CAMSAP1 and affects its ability to bind to MTs, which in turn changes the protection of MT minus-ends and also triggers asymmetric distribution of MTs. Our results indicate that the polarized MT network in neurons is a decisive factor in establishing axon/dendritic polarity and is initially triggered by polarized signals.

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Carmichael, Stephen W., and W. Stephen Brimijoin. "Looking at Slow Axonal Transport." Microscopy Today 4, no. 9 (November 1996): 3–5. http://dx.doi.org/10.1017/s1551929500065299.

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Neurons are about as polarized as cells ever get. Their axonal process can extend a distance that is up to a million times the diameter of the nerve cell body. Axons have none of the ribosomal machinery responsible for protein synthesis, so all neuronal proteins and peptides must be manufactured near the nucleus and carried out to the periphery. This distribution involves at least two distinct mechanisms, fast axonal transport, moving at almost 500 mm per day, and slow axonal transport, moving only 0.1 to 3 mm per day. It turns out that proteins of the neuronal cytoskeleton, along with many soluble cytosolic proteins, are transported exclusively by the slower process.

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Poyatos, Irene, Francesca Ruberti, Rodrigo Martı́nez-Maza, Cecilio Giménez, Carlos G. Dotti, and Francisco Zafra. "Polarized Distribution of Glycine Transporter Isoforms in Epithelial and Neuronal Cells." Molecular and Cellular Neuroscience 15, no. 1 (January 2000): 99–111. http://dx.doi.org/10.1006/mcne.1999.0807.

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Simon, Anne C., Claude Loverdo, Anne-Lise Gaffuri, Michel Urbanski, Delphine Ladarre, Damien Carrel, Isabelle Rivals, et al. "Activation-dependent plasticity of polarized GPCR distribution on the neuronal surface." Journal of Molecular Cell Biology 5, no. 4 (April 11, 2013): 250–65. http://dx.doi.org/10.1093/jmcb/mjt014.

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Lalli, Giovanna. "Crucial polarity regulators in axon specification." Essays in Biochemistry 53 (August 28, 2012): 55–68. http://dx.doi.org/10.1042/bse0530055.

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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.

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Zhang, Xiaoyu, Erfei Bi, Peter Novick, Lilin Du, Keith G. Kozminski, Joshua H. Lipschutz, and Wei Guo. "Cdc42 Interacts with the Exocyst and Regulates Polarized Secretion." Journal of Biological Chemistry 276, no. 50 (October 10, 2001): 46745–50. http://dx.doi.org/10.1074/jbc.m107464200.

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Polarized delivery and incorporation of proteins and lipids to specific domains of the plasma membrane is fundamental to a wide range of biological processes such as neuronal synaptogenesis and epithelial cell polarization. The exocyst complex is specifically localized to sites of active exocytosis and plays essential roles in secretory vesicle targeting and docking at the plasma membrane. Sec3p, a component of the exocyst, is thought to be a spatial landmark for polarized exocytosis. In a search for proteins that regulate the localization of the exocyst in the budding yeastSaccharomyces cerevisiae, we found that certaincdc42mutants affect the polarized localization of the exocyst proteins. In addition, we found that these mutant cells have a randomized protein secretion pattern on the cell surface. Biochemical experiments indicated that Sec3p directly interacts with Cdc42 in its GTP-bound form. Genetic studies demonstrated synthetically lethal interactions betweencdc42and several exocyst mutants. These results have revealed a role for Cdc42 in exocytosis. We propose that Cdc42 coordinates the vesicle docking machinery and the actin cytoskeleton for polarized secretion.

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Stacho, Martin, Christina Herold, Noemi Rook, Hermann Wagner, Markus Axer, Katrin Amunts, and Onur Güntürkün. "A cortex-like canonical circuit in the avian forebrain." Science 369, no. 6511 (September 24, 2020): eabc5534. http://dx.doi.org/10.1126/science.abc5534.

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Although the avian pallium seems to lack an organization akin to that of the cerebral cortex, birds exhibit extraordinary cognitive skills that are comparable to those of mammals. We analyzed the fiber architecture of the avian pallium with three-dimensional polarized light imaging and subsequently reconstructed local and associative pallial circuits with tracing techniques. We discovered an iteratively repeated, column-like neuronal circuitry across the layer-like nuclear boundaries of the hyperpallium and the sensory dorsal ventricular ridge. These circuits are connected to neighboring columns and, via tangential layer-like connections, to higher associative and motor areas. Our findings indicate that this avian canonical circuitry is similar to its mammalian counterpart and might constitute the structural basis of neuronal computation.

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Morena, Francesco, Chiara Argentati, Michelina Soccio, Ilaria Bicchi, Francesca Luzi, Luigi Torre, Andrea Munari, et al. "Unpatterned Bioactive Poly(Butylene 1,4-Cyclohexanedicarboxylate)-Based Film Fast Induced Neuronal-Like Differentiation of Human Bone Marrow-Mesenchymal Stem Cells." International Journal of Molecular Sciences 21, no. 23 (December 4, 2020): 9274. http://dx.doi.org/10.3390/ijms21239274.

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Herein, we present poly(butylene 1,4-cyclohexanedicarboxylate) (PBCE) films characterized by an unpatterned microstructure and a specific hydrophobicity, capable of boosting a drastic cytoskeleton architecture remodeling, culminating with the neuronal-like differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs). We have used two different filming procedures to prepare the films, solvent casting (PBCE) and compression-moulding (PBCE*). PBCE film had a rough and porous surface with spherulite-like aggregations (Ø = 10–20 μm) and was characterized by a water contact angle = 100°. PBCE* showed a smooth and continuous surface without voids and visible spherulite-like aggregations and was more hydrophobic (WCA = 110°). Both surface characteristics were modulated through the copolymerization of different amounts of ether-oxygen-containing co-units into PBCE chemical structure. We showed that only the surface characteristics of PBCE-solvent-casted films steered hBM-MSCs toward a neuronal-like differentiation. hBM-MSCs lost their canonical mesenchymal morphology, acquired a neuronal polarized shape with a long cell protrusion (≥150 μm), expressed neuron-specific class III β-tubulin and microtubule-associated protein 2 neuronal markers, while nestin, a marker of uncommitted stem cells, was drastically silenced. These events were observed as early as 2-days after cell seeding. Of note, the phenomenon was totally absent on PBCE* film, as hBM-MSCs maintained the mesenchymal shape and behavior and did not express neuronal/glial markers.

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Tortosa, Elena, and Casper C. Hoogenraad. "Polarized trafficking: the palmitoylation cycle distributes cytoplasmic proteins to distinct neuronal compartments." Current Opinion in Cell Biology 50 (February 2018): 64–71. http://dx.doi.org/10.1016/j.ceb.2018.02.004.

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Sheen, Volney L. "Periventricular Heterotopia: Shuttling of Proteins through Vesicles and Actin in Cortical Development and Disease." Scientifica 2012 (2012): 1–13. http://dx.doi.org/10.6064/2012/480129.

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During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone. Vesicle trafficking is also required for maintenance of lipid and protein cycling within the leading and trailing edge of migratory neurons, as well as dendrites and synapses of mature neurons. Defects in this transport machinery disrupt neuronal identity, migration, and connectivity and give rise to a malformation of cortical development termed as periventricular heterotopia (PH). PH is characterized by a reduction in brain size, ectopic clusters of neurons localized along the lateral ventricle, and epilepsy and dyslexia. These anatomical anomalies correlate with developmental impairments in neural progenitor proliferation and specification, migration from loss of neuroependymal integrity and neuronal motility, and aberrant neuronal process extension. Genes causal for PH regulate vesicle-mediated endocytosis along an actin cytoskeletal network. This paper explores the role of these dynamic processes in cortical development and disease.

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Bloom, Ona, Julia J. Unternaehrer, Aimin Jiang, Jeong-Sook Shin, Lélia Delamarre, Patrick Allen, and Ira Mellman. "Spinophilin participates in information transfer at immunological synapses." Journal of Cell Biology 181, no. 2 (April 14, 2008): 203–11. http://dx.doi.org/10.1083/jcb.200711149.

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The adaptive immune response is initiated by the presentation of peptides bound to major histocompatibility complex molecules on dendritic cells (DCs) to antigen-specific T lymphocytes at a junction termed the immunological synapse. Although much attention has been paid to cytoplasmic events on the T cell side of the synapse, little is known concerning events on the DC side. We have sought signal transduction components of the neuronal synapse that were also expressed by DCs. One such protein is spinophilin, a scaffolding protein of neuronal dendritic spines that regulates synaptic transmission. In inactive, immature DCs, spinophilin is located throughout the cytoplasm but redistributes to the plasma membrane upon stimulus-induced maturation. In DCs interacting with T cells, spinophilin is polarized dynamically to contact sites in an antigen-dependent manner. It is also required for optimal T cell activation because DCs derived from mice lacking spinophilin exhibit defects in antigen presentation both in vitro and in vivo. Thus, spinophilin may play analogous roles in information transfer at both neuronal and immunological synapses.

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Yan, Dong, Li Guo, and Yizheng Wang. "Requirement of dendritic Akt degradation by the ubiquitin–proteasome system for neuronal polarity." Journal of Cell Biology 174, no. 3 (July 24, 2006): 415–24. http://dx.doi.org/10.1083/jcb.200511028.

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Asymmetric distributions of activities of the protein kinases Akt and glycogen synthase kinase 3β (GSK-3β) are critical for the formation of neuronal polarity. However, the mechanisms underlying polarized regulation of this pathway remain unclear. In this study, we report that the instability of Akt regulated by the ubiquitin–proteasome system (UPS) is required for neuron polarity. Preferential distribution in the axons was observed for Akt but not for its target GSK-3β. A photoactivatable GFP fused to Akt revealed the preferential instability of Akt in dendrites. Akt but not p110 or GSK-3β was ubiquitinated. Suppressing the UPS led to the symmetric distribution of Akt and the formation of multiple axons. These results indicate that local protein degradation mediated by the UPS is important in determining neuronal polarity.

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Hirokawa, Nobutaka. "Molecular architecture and functions of the neuronal cytoskeleton." Proceedings, annual meeting, Electron Microscopy Society of America 48, no. 3 (August 12, 1990): 2–3. http://dx.doi.org/10.1017/s0424820100157541.

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In this symposium I will present our studies about the molecular architecture and function of the cytomatrix of the nerve cells. The nerve cell is a highly polarized cell composed of highly branched dendrites, cell body, and a single long axon along the direction of the impulse propagation. Each part of the neuron takes characteristic shapes for which the cytoskeleton provides the framework. The neuronal cytoskeletons play important roles on neuronal morphogenesis, organelle transport and the synaptic transmission. In the axon neurofilaments (NF) form dense arrays, while microtubules (MT) are arranged as small clusters among the NFs. On the other hand, MTs are distributed uniformly, whereas NFs tend to run solitarily or form small fascicles in the dendrites Quick freeze deep etch electron microscopy revealed various kinds of strands among MTs, NFs and membranous organelles (MO). These structures form major elements of the cytomatrix in the neuron. To investigate molecular nature and function of these filaments first we studied molecular structures of microtubule associated proteins (MAP1A, MAP1B, MAP2, MAP2C and tau), and microtubules reconstituted from MAPs and tubulin in vitro. These MAPs were all fibrous molecules with different length and formed arm like projections from the microtubule surface.

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Gorski, Jessica A., Lisa L. Gomez, John D. Scott, and Mark L. Dell'Acqua. "Association of an A-Kinase-anchoring Protein Signaling Scaffold with Cadherin Adhesion Molecules in Neurons and Epithelial Cells." Molecular Biology of the Cell 16, no. 8 (August 2005): 3574–90. http://dx.doi.org/10.1091/mbc.e05-02-0134.

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A-kinase-anchoring protein (AKAP) 79/150 organizes a scaffold of cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and protein phosphatase 2B/calcineurin that regulates phosphorylation pathways underlying neuronal long-term potentiation and long-term depression (LTD) synaptic plasticity. AKAP79/150 postsynaptic targeting requires three N-terminal basic domains that bind F-actin and acidic phospholipids. Here, we report a novel interaction of these domains with cadherin adhesion molecules that are linked to actin through β-catenin (β-cat) at neuronal synapses and epithelial adherens junctions. Mapping the AKAP binding site in cadherins identified overlap with β-cat binding; however, no competition between AKAP and β-cat binding to cadherins was detected in vitro. Accordingly, AKAP79/150 exhibited polarized localization with β-cat and cadherins in epithelial cell lateral membranes, and β-cat was present in AKAP–cadherin complexes isolated from epithelial cells, cultured neurons, and rat brain synaptic membranes. Inhibition of epithelial cell cadherin adhesion and actin polymerization redistributed intact AKAP–cadherin complexes from lateral membranes to intracellular compartments. In contrast, stimulation of neuronal pathways implicated in LTD that depolymerize postsynaptic F-actin disrupted AKAP–cadherin interactions and resulted in loss of the AKAP, but not cadherins, from synapses. This neuronal regulation of AKAP79/150 targeting to cadherins may be important in functional and structural synaptic modifications underlying plasticity.

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Imbrosci, Barbara, Angela Neitz, and Thomas Mittmann. "Physiological Properties of Supragranular Cortical Inhibitory Interneurons Expressing Retrograde Persistent Firing." Neural Plasticity 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/608141.

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Neurons are polarized functional units. The somatodendritic compartment receives and integrates synaptic inputs while the axon relays relevant synaptic information in form of action potentials (APs) across long distance. Despite this well accepted notion, recent research has shown that, under certain circumstances, the axon can also generate APs independent of synaptic inputs at axonal sites distal from the soma. These ectopic APs travel both toward synaptic terminals and antidromically toward the soma. This unusual form of neuronal communication seems to preferentially occur in cortical inhibitory interneurons following a period of intense neuronal activity and might have profound implications for neuronal information processing. Here we show that trains of ectopically generated APs can be induced in a large portion of neocortical layer 2/3 GABAergic interneurons following a somatic depolarization inducing hundreds of APs. Sparsely occurring ectopic spikes were also observed in a large portion of layer 1 interneurons even in absence of prior somatic depolarization. Remarkably, we found that interneurons which produce ectopic APs display specific membrane and morphological properties significantly different from the remaining GABAergic cells and may therefore represent a functionally unique interneuronal subpopulation.

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Ren, Yi, and Wise Young. "Managing Inflammation after Spinal Cord Injury through Manipulation of Macrophage Function." Neural Plasticity 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/945034.

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Spinal cord injury (SCI) triggers inflammation with activation of innate immune responses that contribute to secondary injury including oligodendrocyte apoptosis, demyelination, axonal degeneration, and neuronal death. Macrophage activation, accumulation, and persistent inflammation occur in SCI. Macrophages are heterogeneous cells with extensive functional plasticity and have the capacity to switch phenotypes by factors present in the inflammatory microenvironment of the injured spinal cord. This review will discuss the role of different polarized macrophages and the potential effect of macrophage-based therapies for SCI.

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McCaig, C. D. "Nerve branching is induced and oriented by a small applied electric field." Journal of Cell Science 95, no. 4 (April 1, 1990): 605–15. http://dx.doi.org/10.1242/jcs.95.4.605.

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Nerve branching is controlled by intrinsic and extrinsic cues, one of which may be a small applied electric field. Lateral processes were induced by passing current through a micropipette placed at 90 degrees to the shaft of a developing nerve. The appearance of processes was a polarised event with a large majority arising from the cathodal facing side of nerves. Whilst an electric field alone may promote branching, the presence of dimethyl sulfoxide (DMSO) or the ganglioside GM1 enhanced branching of developing nerves. It is likely that an applied electric field promotes microtubule disassembly locally along the neurite shaft and that this can lead to a polarised rearrangement of the neuronal cyto-skeleton. It is suggested that the use of an applied electric field in conjunction with these pharmacological agents might enhance nerve regeneration in vivo.

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Toriyama, Michinori, Tadayuki Shimada, Ki Bum Kim, Mari Mitsuba, Eiko Nomura, Kazuhiro Katsuta, Yuichi Sakumura, Peter Roepstorff, and Naoyuki Inagaki. "Shootin1: a protein involved in the organization of an asymmetric signal for neuronal polarization." Journal of Cell Biology 175, no. 1 (October 9, 2006): 147–57. http://dx.doi.org/10.1083/jcb.200604160.

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Neurons have the remarkable ability to polarize even in symmetrical in vitro environments. Although recent studies have shown that asymmetric intracellular signals can induce neuronal polarization, it remains unclear how these polarized signals are organized without asymmetric cues. We describe a novel protein, named shootin1, that became up-regulated during polarization of hippocampal neurons and began fluctuating accumulation among multiple neurites. Eventually, shootin1 accumulated asymmetrically in a single neurite, which led to axon induction for polarization. Disturbing the asymmetric organization of shootin1 by excess shootin1 disrupted polarization, whereas repressing shootin1 expression inhibited polarization. Overexpression and RNA interference data suggest that shootin1 is required for spatially localized phosphoinositide-3-kinase activity. Shootin1 was transported anterogradely to the growth cones and diffused back to the soma; inhibiting this transport prevented its asymmetric accumulation in neurons. We propose that shootin1 is involved in the generation of internal asymmetric signals required for neuronal polarization.

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Hedstrom, Kristian L., Yasuhiro Ogawa, and Matthew N. Rasband. "AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity." Journal of Cell Biology 183, no. 4 (November 10, 2008): 635–40. http://dx.doi.org/10.1083/jcb.200806112.

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The axon initial segment (AIS) functions as both a physiological and physical bridge between somatodendritic and axonal domains. Given its unique molecular composition, location, and physiology, the AIS is thought to maintain neuronal polarity. To identify the molecular basis of this AIS property, we used adenovirus-mediated RNA interference to silence AIS protein expression in polarized neurons. Some AIS proteins are remarkably stable with half-lives of at least 2 wk. However, silencing the expression of the cytoskeletal scaffold ankyrinG (ankG) dismantles the AIS and causes axons to acquire the molecular characteristics of dendrites. Both cytoplasmic- and membrane-associated proteins, which are normally restricted to somatodendritic domains, redistribute into the former axon. Furthermore, spines and postsynaptic densities of excitatory synapses assemble on former axons. Our results demonstrate that the loss of ankG causes axons to acquire the molecular characteristics of dendrites; thus, ankG is required for the maintenance of neuronal polarity and molecular organization of the AIS.

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Pongrakhananon, Varisa, Hiroko Saito, Sylvain Hiver, Takaya Abe, Go Shioi, Wenxiang Meng, and Masatoshi Takeichi. "CAMSAP3 maintains neuronal polarity through regulation of microtubule stability." Proceedings of the National Academy of Sciences 115, no. 39 (September 6, 2018): 9750–55. http://dx.doi.org/10.1073/pnas.1803875115.

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The molecular mechanisms that guide each neuron to become polarized, forming a single axon and multiple dendrites, remain unknown. Here we show that CAMSAP3 (calmodulin-regulated spectrin-associated protein 3), a protein that regulates the minus-end dynamics of microtubules, plays a key role in maintaining neuronal polarity. In mouse hippocampal neurons, CAMSAP3 was enriched in axons. Although axonal microtubules were generally acetylated, CAMSAP3 was preferentially localized along a less-acetylated fraction of the microtubules. CAMSAP3-mutated neurons often exhibited supernumerary axons, along with an increased number of neurites having nocodazole-resistant/acetylated microtubules compared with wild-type neurons. Analysis using cell lines showed that CAMSAP3 depletion promoted tubulin acetylation, and conversely, mild overexpression of CAMSAP3 inhibited it, suggesting that CAMSAP3 works to retain nonacetylated microtubules. In contrast, CAMSAP2, a protein related to CAMSAP3, was detected along all neurites, and its loss did not affect neuronal polarity, nor did it cause increased tubulin acetylation. Depletion of α-tubulin acetyltransferase-1 (αTAT1), the key enzyme for tubulin acetylation, abolished CAMSAP3 loss-dependent multiple-axon formation. These observations suggest that CAMSAP3 sustains a nonacetylated pool of microtubules in axons, interfering with the action of αTAT1, and this process is important to maintain neuronal polarity.

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Sofer, A., G. Schwarzmann, and A. H. Futerman. "The internalization of a short acyl chain analogue of ganglioside GM1 in polarized neurons." Journal of Cell Science 109, no. 8 (August 1, 1996): 2111–19. http://dx.doi.org/10.1242/jcs.109.8.2111.

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In order to study the endocytosis of membrane lipids during the development of neuronal polarity, we examined the internalization of a short acyl chain fluorescent derivative of ganglioside GM1, N-(6-(4-nitrobenz-2-oxa-1,3-diazole-7-yl)-aminohexanoyl)-GM1 (C6-NBD-GM1), in hippocampal neurons cultured at low density. C6-NBD-GM1 was internalized by temperature- and energy-dependent mechanisms, and after short times of incubation, accumulated in endosomes in the axon, cell body and dendrites of neurons maintained for up to 4–5 days in culture. C6-NBD-GM1 was subsequently transported in a retrograde direction to a pool of recycling endosomes in the cell body, with little transport to lysosomes, as indicated by the lack of degradation of C6-NBD-GM1 even after long times, and the re-appearance of intact C6-NBD-GM1 at the cell surface after recycling; similarly, little degradation of C6-NBD-GM1 was detected in N18TG-2 neuroblastoma cells. In hippocampal neurons maintained for longer than 6 days in culture, there was little internalization of C6-NBD-GM1 along the length of axons, but the amount of endocytosis from dendrites was similar to that observed in younger neurons. These results demonstrate that gangliosides turnover rapidly in dendritic membranes at all stages of neuronal development, whereas ganglioside turnover in axons is much less rapid, at least in mature, polarized neurons.

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Nguyen, Michelle M., Christie J. McCracken, E. S. Milner, Daniel J. Goetschius, Alexis T. Weiner, Melissa K. Long, Nick L. Michael, Sean Munro, and Melissa M. Rolls. "γ-Tubulin controls neuronal microtubule polarity independently of Golgi outposts." Molecular Biology of the Cell 25, no. 13 (July 2014): 2039–50. http://dx.doi.org/10.1091/mbc.e13-09-0515.

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Neurons have highly polarized arrangements of microtubules, but it is incompletely understood how microtubule polarity is controlled in either axons or dendrites. To explore whether microtubule nucleation by γ-tubulin might contribute to polarity, we analyzed neuronal microtubules in Drosophila containing gain- or loss-of-function alleles of γ-tubulin. Both increased and decreased activity of γ-tubulin, the core microtubule nucleation protein, altered microtubule polarity in axons and dendrites, suggesting a close link between regulation of nucleation and polarity. To test whether nucleation might locally regulate polarity in axons and dendrites, we examined the distribution of γ-tubulin. Consistent with local nucleation, tagged and endogenous γ-tubulins were found in specific positions in dendrites and axons. Because the Golgi complex can house nucleation sites, we explored whether microtubule nucleation might occur at dendritic Golgi outposts. However, distinct Golgi outposts were not present in all dendrites that required regulated nucleation for polarity. Moreover, when we dragged the Golgi out of dendrites with an activated kinesin, γ-tubulin remained in dendrites. We conclude that regulated microtubule nucleation controls neuronal microtubule polarity but that the Golgi complex is not directly involved in housing nucleation sites.

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Sakakibara, Akira, and Alan F. Horwitz. "Mechanism of polarized protrusion formation on neuronal precursors migrating in the developing chicken cerebellum." Journal of Cell Science 119, no. 17 (August 15, 2006): 3583–92. http://dx.doi.org/10.1242/jcs.03080.

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Guo, Xiaoli, Ginny G. Farías, Rafael Mattera, and Juan S. Bonifacino. "Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon." Proceedings of the National Academy of Sciences 113, no. 36 (August 24, 2016): E5318—E5327. http://dx.doi.org/10.1073/pnas.1601844113.

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An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon. This loss of polarity is not caused primarily by increased transport from the soma to the axon but rather by decreased retrieval from the axon to the soma. Retrieval is also dependent on the Rab5 effector Fused Toes (FTS)–Hook–FTS and Hook-interacting protein (FHIP) (FHF) complex, which interacts with the minus-end–directed microtubule motor dynein and its activator dynactin to drive a population of axonal retrograde carriers containing somatodendritic proteins toward the soma. These findings emphasize the importance of both biosynthetic sorting and axonal retrieval for the polarized distribution of somatodendritic receptors at steady state.

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Nakata, Takao, Shinsuke Niwa, Yasushi Okada, Franck Perez, and Nobutaka Hirokawa. "Preferential binding of a kinesin-1 motor to GTP-tubulin–rich microtubules underlies polarized vesicle transport." Journal of Cell Biology 194, no. 2 (July 18, 2011): 245–55. http://dx.doi.org/10.1083/jcb.201104034.

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Polarized transport in neurons is fundamental for the formation of neuronal circuitry. A motor domain–containing truncated KIF5 (a kinesin-1) recognizes axonal microtubules, which are enriched in EB1 binding sites, and selectively accumulates at the tips of axons. However, it remains unknown what cue KIF5 recognizes to result in this selective accumulation. We found that axonal microtubules were preferentially stained by the anti–GTP-tubulin antibody hMB11. Super-resolution microscopy combined with EM immunocytochemistry revealed that hMB11 was localized at KIF5 attachment sites. In addition, EB1, which binds preferentially to guanylyl-methylene-diphosphate (GMPCPP) microtubules in vitro, recognized hMB11 binding sites on axonal microtubules. Further, expression of hMB11 antibody in neurons disrupted the selective accumulation of truncated KIF5 in the axon tips. In vitro studies revealed approximately threefold stronger binding of KIF5 motor head to GMPCPP microtubules than to GDP microtubules. Collectively, these data suggest that the abundance of GTP-tubulin in axonal microtubules may underlie selective KIF5 localization and polarized axonal vesicular transport.

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Bryant, Winnifred. "Modeling the Effects of Intracellular Anions on Membrane Potential: An Active-Learning Exercise." American Biology Teacher 81, no. 5 (May 1, 2019): 373–76. http://dx.doi.org/10.1525/abt.2019.81.5.373.

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In biological membranes that are permeable to water and ions but impermeable to other solutes, the diffusible ions cannot reach a concentration equilibrium. Instead, a state of electroneutrality is achieved on each side of the membrane, which requires that the diffusible ions be found in different concentrations on either side of the membrane. The Donnan equilibrium is a major contributing factor to the polarized state of cells, and appreciating it is vital to the understanding of neuronal physiology. This article presents a nonmathematical active-learning exercise that will help AP and college biology students understand how the Donnan equilibrium is achieved.

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Hatakeyama, Masahiro, Itaru Ninomiya, Yutaka Otsu, Kaoru Omae, Yasuko Kimura, Osamu Onodera, Masanori Fukushima, Takayoshi Shimohata, and Masato Kanazawa. "Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review." International Journal of Molecular Sciences 21, no. 17 (August 27, 2020): 6194. http://dx.doi.org/10.3390/ijms21176194.

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Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

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Huntwork-Rodriguez, Sarah, Bei Wang, Trent Watkins, Arundhati Sengupta Ghosh, Christine D. Pozniak, Daisy Bustos, Kim Newton, Donald S. Kirkpatrick, and Joseph W. Lewcock. "JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis." Journal of Cell Biology 202, no. 5 (August 26, 2013): 747–63. http://dx.doi.org/10.1083/jcb.201303066.

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Neurons are highly polarized cells that often project axons a considerable distance. To respond to axonal damage, neurons must transmit a retrograde signal to the nucleus to enable a transcriptional stress response. Here we describe a mechanism by which this signal is propagated through injury-induced stabilization of dual leucine zipper-bearing kinase (DLK/MAP3K12). After neuronal insult, specific sites throughout the length of DLK underwent phosphorylation by c-Jun N-terminal kinases (JNKs), which have been shown to be downstream targets of DLK pathway activity. These phosphorylation events resulted in increased DLK abundance via reduction of DLK ubiquitination, which was mediated by the E3 ubiquitin ligase PHR1 and the de-ubiquitinating enzyme USP9X. Abundance of DLK in turn controlled the levels of downstream JNK signaling and apoptosis. Through this feedback mechanism, the ubiquitin–proteasome system is able to provide an additional layer of regulation of retrograde stress signaling to generate a global cellular response to localized external insults.

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Goldmann, Tobias, and Marco Prinz. "Role of Microglia in CNS Autoimmunity." Clinical and Developmental Immunology 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/208093.

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Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) in the Western world. The disease is characterized histologically by the infiltration of encephalitogenicTH1/TH17-polarized CD4+T cells, B cells, and a plethora of myeloid cells, resulting in severe demyelination ultimately leading to a degeneration of neuronal structures. These pathological processes are substantially modulated by microglia, the resident immune competent cells of the CNS. In this overview, we summarize the current knowledge regarding the highly diverse and complex function of microglia during CNS autoimmunity in either promoting tissue injury or tissue repair. Hence, understanding microglia involvement in MS offers new exciting paths for therapeutic intervention.

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John Cork, R., and Ann M. Rajnicek. "Computer-aided analysis of polarized neurite growth effects of applied electrical fields on neuronal development." Journal of Neuroscience Methods 32, no. 1 (April 1990): 45–54. http://dx.doi.org/10.1016/0165-0270(90)90070-v.

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Billaud, Gilberte, Jean Costentin, and Jean-Jacques Bonnet. "Specific binding of [3H]GBR 12783 to the dopamine neuronal carrier included in polarized membranes." European Journal of Pharmacology: Molecular Pharmacology 247, no. 3 (November 1993): 333–40. http://dx.doi.org/10.1016/0922-4106(93)90203-l.

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Sample, Vedangi, Santosh Ramamurthy, Kirill Gorshkov, Gabriele V. Ronnett, and Jin Zhang. "Polarized activities of AMPK and BRSK in primary hippocampal neurons." Molecular Biology of the Cell 26, no. 10 (May 15, 2015): 1935–46. http://dx.doi.org/10.1091/mbc.e14-02-0764.

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5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master metabolic regulator that has been shown to inhibit the establishment of neuronal polarity/axogenesis under energy stress conditions, whereas brain-specific kinase (BRSK) promotes the establishment of axon-dendrite polarity and synaptic development. However, little information exists regarding the localized activity and regulation of these kinases in developing neurons. In this study, using a fluorescence resonance energy transfer (FRET)-based activity reporter that responds to both AMPK and BRSK, we found that BRSK activity is elevated in the distal region of axons in polarized hippocampal neurons before any stimulation and does not respond to either Ca2+ or 2-deoxyglucose (2-DG) stimulation. In contrast, AMPK activity is stimulated by either Ca2+ or 2-DG in the soma, dendrites, and axons of hippocampal neurons, with maximal stimulated activity observed in the distal region of the axon. Our study shows that the activities of both AMPK and BRSK are polarized in developing hippocampal neurons, with high levels in the distal region of extended axons.

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Johnson, Hong W., and Michael J. Schell. "Neuronal IP3 3-Kinase is an F-actin–bundling Protein: Role in Dendritic Targeting and Regulation of Spine Morphology." Molecular Biology of the Cell 20, no. 24 (December 15, 2009): 5166–80. http://dx.doi.org/10.1091/mbc.e09-01-0083.

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The actin microstructure in dendritic spines is involved in synaptic plasticity. Inositol trisphosphate 3-kinase A (ITPKA) terminates Ins(1,4,5)P3 signals emanating from spines and also binds filamentous actin (F-actin) through its amino terminal region (amino acids 1-66, N66). Here we investigated how ITPKA, independent of its kinase activity, regulates dendritic spine F-actin microstructure. We show that the N66 region of the protein mediates F-actin bundling. An N66 fusion protein bundled F-actin in vitro, and the bundling involved N66 dimerization. By mutagenesis we identified a point mutation in a predicted helical region that eliminated both F-actin binding and bundling, rendering the enzyme cytosolic. A fusion protein containing a minimal helical region (amino acids 9-52, N9-52) bound F-actin in vitro and in cells, but had lower affinity. In hippocampal neurons, GFP-tagged N66 expression was highly polarized, with targeting of the enzyme predominantly to spines. By contrast, N9-52-GFP expression occurred in actin-rich structures in dendrites and growth cones. Expression of N66-GFP tripled the length of dendritic protrusions, induced longer dendritic spine necks, and induced polarized actin motility in time-lapse assays. These results suggest that, in addition to its ability to regulate intracellular Ca2+ via Ins(1,4,5)P3 metabolism, ITPKA regulates structural plasticity.

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Diering, Graham H., Yuka Numata, Steven Fan, John Church, and Masayuki Numata. "Endosomal acidification by Na+/H+ exchanger NHE5 regulates TrkA cell-surface targeting and NGF-induced PI3K signaling." Molecular Biology of the Cell 24, no. 21 (November 2013): 3435–48. http://dx.doi.org/10.1091/mbc.e12-06-0445.

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To facilitate polarized vesicular trafficking and signal transduction, neuronal endosomes have evolved sophisticated mechanisms for pH homeostasis. NHE5 is a member of the Na+/H+ exchanger family and is abundantly expressed in neurons and associates with recycling endosomes. Here we show that NHE5 potently acidifies recycling endosomes in PC12 cells. NHE5 depletion by plasmid-based short hairpin RNA significantly reduces cell surface abundance of TrkA, an effect similar to that observed after treatment with the V-ATPase inhibitor bafilomycin. A series of cell-surface biotinylation experiments suggests that anterograde trafficking of TrkA from recycling endosomes to plasma membrane is the likeliest target affected by NHE5 depletion. NHE5 knockdown reduces phosphorylation of Akt and Erk1/2 and impairs neurite outgrowth in response to nerve growth factor (NGF) treatment. Of interest, although both phosphoinositide 3-kinase–Akt and Erk signaling are activated by NGF-TrkA, NGF-induced Akt-phosphorylation appears to be more sensitively affected by perturbed endosomal pH. Furthermore, NHE5 depletion in rat cortical neurons in primary culture also inhibits neurite formation. These results collectively suggest that endosomal pH modulates trafficking of Trk-family receptor tyrosine kinases, neurotrophin signaling, and possibly neuronal differentiation.

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Zlatic, Stephanie A., Karine Tornieri, Steven W. L’Hernault, and Victor Faundez. "Clathrin-dependent mechanisms modulate the subcellular distribution of class C Vps/HOPS tether subunits in polarized and nonpolarized cells." Molecular Biology of the Cell 22, no. 10 (May 15, 2011): 1699–715. http://dx.doi.org/10.1091/mbc.e10-10-0799.

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Coats define the composition of carriers budding from organelles. In addition, coats interact with membrane tethers required for vesicular fusion. The yeast AP-3 (Adaptor Protein Complex 3) coat and the class C Vps/HOPS (HOmotypic fusion and Protein Sorting) tether follow this model as their interaction occurs at the carrier fusion step. Here we show that mammalian Vps class C/HOPS subunits and clathrin interact and that acute perturbation of clathrin function disrupts the endosomal distribution of Vps class C/HOPS tethers in HEK293T and polarized neuronal cells. Vps class C/HOPS subunits and clathrin exist in complex with either AP-3 or hepatocyte growth factor receptor substrate (Hrs). Moreover, Vps class C/HOPS proteins cofractionate with clathrin-coated vesicles, which are devoid of Hrs. Expression of FK506 binding protein (FKBP)–clathrin light chain chimeras, to inhibit clathrin membrane association dynamics, increased Vps class C/HOPS subunit content in rab5 endosomal compartments. Additionally, Vps class C/HOPS subunits were concentrated at tips of neuronal processes, and their delivery was impaired by expression of FKBP–clathrin chimeras and AP20187 incubation. These data support a model in which Vps class C/HOPS subunits incorporate into clathrin-coated endosomal domains and carriers in mammalian cells. We propose that vesicular (AP-3) and nonvesicular (Hrs) clathrin mechanisms segregate class C Vps/HOPS tethers to organelles and domains of mammalian cells bearing complex architectures.

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Li, Huihui, Zak Doric, Amandine Berthet, Danielle M. Jorgens, Mai K. Nguyen, Ivy Hsieh, Julia Margulis, et al. "Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation." Science Advances 7, no. 32 (August 2021): eabf6580. http://dx.doi.org/10.1126/sciadv.abf6580.

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Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson’s disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration.

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Granatiero, Veronica, and Giovanni Manfredi. "Mitochondrial Transport and Turnover in the Pathogenesis of Amyotrophic Lateral Sclerosis." Biology 8, no. 2 (May 11, 2019): 36. http://dx.doi.org/10.3390/biology8020036.

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Neurons are high-energy consuming cells, heavily dependent on mitochondria for ATP generation and calcium buffering. These mitochondrial functions are particularly critical at specific cellular sites, where ionic currents impose a large energetic burden, such as at synapses. The highly polarized nature of neurons, with extremely large axoplasm relative to the cell body, requires mitochondria to be efficiently transported along microtubules to reach distant sites. Furthermore, neurons are post-mitotic cells that need to maintain pools of healthy mitochondria throughout their lifespan. Hence, mitochondrial transport and turnover are essential processes for neuronal survival and function. In neurodegenerative diseases, the maintenance of a healthy mitochondrial network is often compromised. Numerous lines of evidence indicate that mitochondrial impairment contributes to neuronal demise in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), where degeneration of motor neurons causes a fatal muscle paralysis. Dysfunctional mitochondria accumulate in motor neurons affected by genetic or sporadic forms of ALS, strongly suggesting that the inability to maintain a healthy pool of mitochondria plays a pathophysiological role in the disease. This article critically reviews current hypotheses on mitochondrial involvement in the pathogenesis of ALS, focusing on the alterations of mitochondrial axonal transport and turnover in motor neurons.

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Iqbal, Anila, Marta Baldrighi, Jennifer N. Murdoch, Angeleen Fleming, and Christopher J. Wilkinson. "Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome." Biology Open 9, no. 10 (September 2, 2020): bio054338. http://dx.doi.org/10.1242/bio.054338.

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ABSTRACTProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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Parton, R. G., C. G. Dotti, R. Bacallao, I. Kurtz, K. Simons, and K. Prydz. "pH-induced microtubule-dependent redistribution of late endosomes in neuronal and epithelial cells." Journal of Cell Biology 113, no. 2 (April 15, 1991): 261–74. http://dx.doi.org/10.1083/jcb.113.2.261.

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The interaction between late endocytic structures and microtubules in polarized cells was studied using a procedure previously shown to cause microtubule-dependent redistribution of lysosomes in fibroblasts and macrophages (Heuser, J. 1989. J. Cell Biol. 108:855-864). In cultured rat hippocampal neurons, low cytoplasmic pH caused cation-independent mannose-6-phosphate receptor-enriched structures to move out of the cell body and into the processes. In filter grown MDCK cells lowering the cytosolic pH to approximately 6.5 caused late endosomes to move to the base of the cell and this process was shown to be microtubule dependent. Alkalinization caused a shift in distribution towards the apical pole of the cell. The results are consistent with low pH causing the redistribution of late endosomes towards the plus ends of the microtubules. In MDCK cells the microtubules orientated vertically in the cell may play a role in this process. The shape changes that accompanied the redistribution of the late endosomes in MDCK cells were examined by electron microscopy. On low pH treatment fragmentation of the late endosomes was observed whereas after microtubule depolymerization individual late endosomal structures appeared to fuse together. The late endosomes of the MDCK cell appear to be highly pleomorphic and dependent on microtubules for their form and distribution in the cell.

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Damisah, Eyiyemisi C., Robert A. Hill, Anupama Rai, Fuyi Chen, Carla V. Rothlin, Sourav Ghosh, and Jaime Grutzendler. "Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo." Science Advances 6, no. 26 (June 2020): eaba3239. http://dx.doi.org/10.1126/sciadv.aba3239.

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Cell death is prevalent throughout life; however, the coordinated interactions and roles of phagocytes during corpse removal in the live brain are poorly understood. We developed photochemical and viral methodologies to induce death in single cells and combined this with intravital optical imaging. This approach allowed us to track multicellular phagocytic interactions with precise spatiotemporal resolution. Astrocytes and microglia engaged with dying neurons in an orchestrated and synchronized fashion. Each glial cell played specialized roles: Astrocyte processes rapidly polarized and engulfed numerous small dendritic apoptotic bodies, while microglia migrated and engulfed the soma and apical dendrites. The relative involvement and phagocytic specialization of each glial cell was plastic and controlled by the receptor tyrosine kinase Mertk. In aging, there was a marked delay in apoptotic cell removal. Thus, a precisely orchestrated response and cross-talk between glial cells during corpse removal may be critical for maintaining brain homeostasis.

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Chow, Woon N., David G. Simpson, John W. Bigbee, and Raymond J. Colello. "Evaluating neuronal and glial growth on electrospun polarized matrices: bridging the gap in percussive spinal cord injuries." Neuron Glia Biology 3, no. 2 (May 2007): 119–26. http://dx.doi.org/10.1017/s1740925x07000580.

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AbstractOne of the many obstacles to spinal cord repair following trauma is the formation of a cyst that impedes axonal regeneration. Accordingly, we examined the potential use of electrospinning to engineer an implantable polarized matrix for axonal guidance. Polydioxanone, a resorbable material, was electrospun to fabricate matrices possessing either aligned or randomly oriented fibers. To assess the extent to which fiber alignment influences directional neuritic outgrowth, rat dorsal root ganglia (DRGs) were cultured on these matrices for 10 days. Using confocal microscopy, neurites displayed a directional growth that mimicked the fiber alignment of the underlying matrix. Because these matrices are generated from a material that degrades with time, we next determined whether a glial substrate might provide a more stable interface between the resorbable matrix and the outgrowing axons. Astrocytes seeded onto either aligned or random matrices displayed a directional growth pattern similar to that of the underlying matrix. Moreover, these glia-seeded matrices, once co-cultured with DRGs, conferred the matrix alignment to and enhanced outgrowth exuberance of the extending neurites. These experiments demonstrate the potential for electrospinning to generate an aligned matrix that influences both the directionality and growth dynamics of DRG neurites.

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Cavaretta, John P., Kaitlyn R. Sherer, Kwan Young Lee, Edward H. Kim, Rodal S. Issema, and Hee Jung Chung. "Polarized Axonal Surface Expression of Neuronal KCNQ Potassium Channels Is Regulated by Calmodulin Interaction with KCNQ2 Subunit." PLoS ONE 9, no. 7 (July 31, 2014): e103655. http://dx.doi.org/10.1371/journal.pone.0103655.

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Bockhorst, Tobias, and Uwe Homberg. "Interaction of compass sensing and object-motion detection in the locust central complex." Journal of Neurophysiology 118, no. 1 (July 1, 2017): 496–506. http://dx.doi.org/10.1152/jn.00927.2016.

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Goal-directed behavior is often complicated by unpredictable events, such as the appearance of a predator during directed locomotion. This situation requires adaptive responses like evasive maneuvers followed by subsequent reorientation and course correction. Here we study the possible neural underpinnings of such a situation in an insect, the desert locust. As in other insects, its sense of spatial orientation strongly relies on the central complex, a group of midline brain neuropils. The central complex houses sky compass cells that signal the polarization plane of skylight and thus indicate the animal’s steering direction relative to the sun. Most of these cells additionally respond to small moving objects that drive fast sensory-motor circuits for escape. Here we investigate how the presentation of a moving object influences activity of the neurons during compass signaling. Cells responded in one of two ways: in some neurons, responses to the moving object were simply added to the compass response that had adapted during continuous stimulation by stationary polarized light. By contrast, other neurons disadapted, i.e., regained their full compass response to polarized light, when a moving object was presented. We propose that the latter case could help to prepare for reorientation of the animal after escape. A neuronal network based on central-complex architecture can explain both responses by slight changes in the dynamics and amplitudes of adaptation to polarized light in CL columnar input neurons of the system. NEW & NOTEWORTHY Neurons of the central complex in several insects signal compass directions through sensitivity to the sky polarization pattern. In locusts, these neurons also respond to moving objects. We show here that during polarized-light presentation, responses to moving objects override their compass signaling or restore adapted inhibitory as well as excitatory compass responses. A network model is presented to explain the variations of these responses that likely serve to redirect flight or walking following evasive maneuvers.

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Pablo, Juan Lorenzo, Chaojian Wang, Matthew M. Presby, and Geoffrey S. Pitt. "Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action." Proceedings of the National Academy of Sciences 113, no. 19 (April 4, 2016): E2665—E2674. http://dx.doi.org/10.1073/pnas.1521194113.

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Clustering of voltage-gated sodium channels (VGSCs) within the neuronal axon initial segment (AIS) is critical for efficient action potential initiation. Although initially inserted into both somatodendritic and axonal membranes, VGSCs are concentrated within the axon through mechanisms that include preferential axonal targeting and selective somatodendritic endocytosis. How the endocytic machinery specifically targets somatic VGSCs is unknown. Here, using knockdown strategies, we show that noncanonical FGF13 binds directly to VGSCs in hippocampal neurons to limit their somatodendritic surface expression, although exerting little effect on VGSCs within the AIS. In contrast, homologous FGF14, which is highly concentrated in the proximal axon, binds directly to VGSCs to promote their axonal localization. Single-point mutations in FGF13 or FGF14 abrogating VGSC interaction in vitro cannot support these specific functions in neurons. Thus, our data show how the concerted actions of FGF13 and FGF14 regulate the polarized localization of VGSCs that supports efficient action potential initiation.

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Journal articles on the topic 'POLARIDAD NEURONAL'

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