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1.
Neuronal polarization, the formation of one long axon and several short dendrites, is an obligatory process to integrate and propagate information within the brain. Axon formation is the key event during neuronal polarization and is based on tightly regulated rearrangements of the cytoskeleton. Here, we discuss how the cytoskeleton drives neuronal polarization. First, we convey the role of the actin cytoskeleton and microtubules during axon formation. Second, we discuss different cytoskeletal binding and regulating proteins, which are essential to specify the axon. Finally, we outline plus end tracking proteins (+TIPs) as important regulators for neuronal polarization by mediating the interaction between the actin cytoskeleton and microtubules and compare this function to other polarity processes. 相似文献
2.
G Lalli 《Essays in biochemistry》2012,53(1):55-68
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. 相似文献
3.
Neuronal polarization: the cytoskeleton leads the way 总被引:1,自引:0,他引:1
The morphology of cells is key to their function. Neurons extend a long axon and several shorter dendrites to transmit signals in the nervous system. This process of neuronal polarization is driven by the cytoskeleton. The first and decisive event during neuronal polarization is the specification of the axon. Distinct cytoskeletal dynamics and organization of the cytoskeleton determine the future axon while the other neurites become dendrites. Here, we will review how the cytoskeleton and its effectors drive axon specification and neuronal polarization. First, the role of the actin cytoskeleton and microtubules in axon specification will be presented. Then, we will discuss the role of the centrosome in axon determination as well as how microtubules are generated in axons and dendrites. Finally, we will discuss potential mechanisms leading to axon specification, such as positive feedback loops that could be a coordinated interaction between actin and microtubules. Together, this review will present the recent advances on the role of the microtubules and the actin cytoskeleton during neuronal polarization. We will pinpoint the upcoming challenges to gain a better understanding of neuronal polarization on a fundamental intracellular level. Finally, we will outline how reactivation of the intrinsic polarization program may help to induce axon regeneration after CNS injury. 相似文献
4.
The formation of axon/dendrite polarity is critical for the neuron to perform its signaling function in the brain. Recent advance in our understanding of cellular and molecular mechanisms underlying the development and maintenance of neuronal polarity has been greatly facilitated by the use of the culture system of dissociated hippocampal neurons. Among many polarization-related proteins, we here focus on the mammalian LKB1, the counterpart of the C. elegans Par-4, which is an upstream regulator among six Par (partitioning-defective) genes that act as master regulators of cell polarity in different cell types across evolutionary distant species. Recent studies have identified LKB1 and its downstream targets SAD/MARK kinases (mammalian homologs of Par-1) as key regulators of neuronal polarization and axon development in cultured neurons and in developing cortical neurons in vivo. We will review the properties of and interactions among proteins in this LKB1-SAD/MARK pathway, drawing upon information obtained from both neuronal and non-neuronal systems. Due to central role of the protein kinase A-dependent phosphorylation of LKB1 in the activation of this pathway, we will review recent findings on how cAMP and cGMP signaling may serve as antagonistic second messengers for axon/dendrite development, and how these cyclic nucleotides may mediate the action of extracellular polarizing factors by modulating the activity of the LKB1-SAD/MARK pathway. 相似文献
5.
The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Important progress has been made toward the identification of the molecular mechanisms regulating neuronal polarization using primarily in vitro approaches such as dissociated culture of rodent hippocampal neurons. The predominant view emerging from this paradigm is that neuronal polarization is initiated by intrinsic activation of signaling pathways underlying the initial break in neuronal symmetry that precedes the future asymmetric growth of the axon. Recent evidence shows that (i) axon-dendrite polarization is specified when neurons engage migration in vivo, (ii) that a kinase pathway defined by LKB1and SAD-kinases (Par4/Par1 dyad) is required for proper neuronal polarization in vivo and that (iii) extracellular cues can play an instructive role during neuronal polarization. Here, we review some of these recent results and highlight future challenges in the field including the determination of how extracellular cues control intracellular responses underlying neuronal polarization in vivo. 相似文献
6.
Chen C Wirth A Ponimaskin E 《The international journal of biochemistry & cell biology》2012,44(3):447-451
Regulation of neuronal morphology and activity-dependent synaptic modifications involves reorganization of the actin cytoskeleton. Dynamic changes of the actin cytoskeleton in many cell types are controlled by small GTPases of the Rho family, such as RhoA, Rac1 and Cdc42. As key regulators of both actin and microtubule cytoskeleton, Rho GTPases have also emerged as important regulators of dendrite and spine structural plasticity. Multiple studies suggest that Rac1 and Cdc42 are positive regulators promoting neurite outgrowth and growth cone protrusion, while the activation of RhoA induces stress fiber formation, leading to growth cone collapse and neurite retraction. This review focuses on recent advances in our understanding of the molecular mechanisms underlying physiological and pathological functions of Cdc42 in the nervous system. We also discuss application of different FRET-based biosensors as a powerful approach to examine the dynamics of Cdc42 activity in living cells. 相似文献
7.
8.
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-3beta 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. 相似文献
9.
Peris B Gonzalez-Granero S Ballester-Lurbe B García-Verdugo JM Pérez-Roger I Guerri C Terrado J Guasch RM 《Journal of neurochemistry》2012,121(6):903-914
Proper development of neuronal networks relies on the polarization of the neurons, thus the establishment of two compartments, axons and dendrites, whose formation depends on cytoskeletal rearrangements. Rnd proteins are regulators of actin organization and they are important players in several aspects of brain development as neurite formation, axon guidance and neuron migration. We have recently demonstrated that mice lacking RhoE/Rnd3 expression die shortly after birth and have neuromotor impairment and neuromuscular alterations, indicating an abnormal development of the nervous system. In this study, we have further investigated the specific role played by RhoE in several aspects of neuronal development by using hippocampal neuron cultures. Our findings show that neurons from a mice lacking RhoE expression exhibit a decrease in the number and the total length of the neurites. We also show that RhoE-deficient neurons display a reduction in axon outgrowth and a delay in the process of neuronal polarization. In addition, our results suggest an involvement of the RHOA/ROCK/LIMK/COFILIN signaling pathway in the neuronal alterations induced by the lack of RhoE. These findings support our previous report revealing the important role of RhoE in the normal development of the nervous system and may provide novel therapeutic targets in neurodegenerative disorders. 相似文献
10.
Neurons are polarized cells that extend a single axon and several dendrites. Historically, how neurons establish their axon-dendrite polarity has been extensively studied using dissociated hippocampal cells in culture. Although such studies have identified the cellular and molecular mechanisms underlying axon-dendrite polarization, the conclusions have been limited to in vitro conditions. Recent progress using live imaging has enabled us to directly observe axon formation in situ, revealing distinct cellular mechanisms that regulate axon-dendrite polarization in vivo. In this review, we compare the cellular events during axon formation studied in various systems both in vivo and in vitro and discuss possible common mechanisms underlying the axon-dendrite polarization. 相似文献
11.
Kessels MM Schwintzer L Schlobinski D Qualmann B 《European journal of cell biology》2011,90(11):926-933
Coordinated functions of the actin cytoskeleton and microtubules, which need to be carefully controlled in time and space, are required for the drastic alterations of neuronal morphology during neuromorphogenesis and neuronal network formation. A key process in neuronal actin dynamics is filament formation by actin nucleators, such as the Arp2/3 complex, formins and the brain-enriched, novel WH2 domain-based nucleators Spire and cordon-bleu (Cobl). We here discuss in detail the currently available data on the roles of these actin nucleators during neuromorphogenesis and highlight how their required control at the plasma membrane may be brought about. The Arp2/3 complex was found to be especially important for proper growth cone translocation and axon development. The underlying molecular mechanisms for Arp2/3 complex activation at the neuronal plasma membrane include a recruitment and an activation of N-WASP by lipid- and F-actin-binding adaptor proteins, Cdc42 and phosphatidyl-inositol-(4,5)-bisphosphate (PIP(2)). Together, these components upstream of N-WASP and the Arp2/3 complex ensure fine-control of N-WASP-mediated Arp2/3 complex activation and control distinct functions during axon development. They are counteracted by Arp2/3 complex inhibitors, such as PICK, which likewise play an important role in neuromorphogenesis. In contrast to the crucial role of the Arp2/3 complex in proper axon development, dendrite formation and dendritic arborization was revealed to critically involve the newly identified actin nucleator Cobl. Cobl is a brain-enriched protein and uses three Wiskott-Aldrich syndrome protein homology 2 (WH2) domains for actin binding and for promoting the formation of non-bundled, unbranched filaments. Thus, cells use different actin nucleators to steer the complex remodeling processes underlying cell morphogenesis, the formation of cellular networks and the development of complex body plans. 相似文献
12.
Neurons are highly polarized cells, most of which develop a single axon and several dendrites. These two compartments acquire specific characteristics that enable neurons to transmit intercellular signals from several dendrites to an axon. A wealth of recent studies has shown that PI 3-kinase, Rho family GTPases, the Par complex, and cytoskeleton-related proteins participate in the initial events of neuronal polarization. Here, we review the role of polarity-regulating molecules and the potential mechanisms underlying the specification of an axon and dendrites. 相似文献
13.
Susanne-Filiz Önel 《Central European Journal of Biology》2009,4(1):11-18
Skeletal muscle formation, growth and repair depend on myoblast fusion events. Therefore, in-depth understanding of the underlying
molecular mechanisms controlling these events that ultimately lead to skeletal muscle formation may be fundamental for developing
new therapies for tissue repair. To this end, the greatest advances in furthering understanding myoblast fusion has been made
in Drosophila. Recent studies have shown that transient F-actin structures, so-called actin plugs or foci, are known to form at the site
of contacting myoblasts. Indeed, actin regulators of the WASP family that control the activation of the Arp2/3 complex and
thereby branched F-actin formation have been demonstrated to be crucial for myoblast fusion. Myoblast-specific cell adhesion
molecules seem to be involved in the recruitment of WASP family members to the site of myoblast fusion and form a Fusion-Restricted
Myogenic-Adhesive Structure (FuRMAS). Currently, the exact role of the FuRMAS is not completely understood. However, recent
studies indicate that WASP-dependent F-actin regulation is required for fusion pore formation as well as for the correct integration
of fusing myoblasts into the growing muscle. In this review, I discuss latest cellular studies, and recent genetic and biochemical
analyses on actin regulation during myoblast fusion. 相似文献
14.
Ena/VASP Is Required for neuritogenesis in the developing cortex 总被引:3,自引:0,他引:3
Kwiatkowski AV Rubinson DA Dent EW Edward van Veen J Leslie JD Zhang J Mebane LM Philippar U Pinheiro EM Burds AA Bronson RT Mori S Fässler R Gertler FB 《Neuron》2007,56(3):441-455
Mammalian cortical development involves neuronal migration and neuritogenesis; this latter process forms the structural precursors to axons and dendrites. Elucidating the pathways that regulate the cytoskeleton to drive these processes is fundamental to our understanding of cortical development. Here we show that loss of all three murine Ena/VASP proteins, a family of actin regulatory proteins, causes neuronal ectopias, alters intralayer positioning in the cortical plate, and, surprisingly, blocks axon fiber tract formation during corticogenesis. Cortical fiber tract defects in the absence of Ena/VASP arise from a failure in neurite initiation, a prerequisite for axon formation. Neurite initiation defects in Ena/VASP-deficient neurons are preceded by a failure to form bundled actin filaments and filopodia. These findings provide insight into the regulation of neurite formation and the role of the actin cytoskeleton during cortical development. 相似文献
15.
With the identification of the molecular determinants of neuronal connectivity, our understanding of the extracellular information that controls axon guidance and synapse formation has evolved from single factors towards the complexity that neurons face in a living organism. As we move in this direction - ready to see the forest for the trees - attention is returning to one of the most ancient regulators of cell-cell interaction: the extracellular matrix. Among many matrix components that influence neuronal connectivity, recent studies of the heparan sulfate proteoglycans suggest that these ancient molecules function as versatile extracellular scaffolds that both sculpt the landscape of extracellular cues and modulate the way that neurons perceive the world around them. 相似文献
16.
A hallmark of neurons is their ability to polarize with dendrite and axon specification to allow the proper flow of information through the nervous system. Over the past decade, extensive research has been performed in an attempt to understand the molecular and cellular machinery mediating this neuronal polarization process. It has become evident that many of the critical regulators involved in establishing neuronal polarity are evolutionarily conserved proteins that had previously been implicated in controlling the polarization of other cell types. At the forefront of this research are the partition defective (Par) proteins. In this review,we will provide a commentary on the progress of work regarding the central importance of Parproteins in the establishment of neuronal polarity. 相似文献
17.
The assembly of functional neuronal networks in the developing animal relies on the polarization of neurons, i.e., the formation of a single axon and multiple dendrites. Breaking the symmetry of neurons depends on cytoskeletal rearrangements. In particular, axon specification requires local dynamic instability of actin and stabilization of microtubules. The polarized cytoskeleton also provides the basis for selective trafficking and retention of cellular components in the future somatodendritic or axonal compartments. Hence, these mechanisms are not only essential to achieve neuronal polarization, but also to maintain it. Different extracellular and intracellular signals converge on the regulation of the cytoskeleton. Most notably, Rho GTPases, PI3K, Ena/VASP, cofilin and SAD kinases are major intracellular regulators of neuronal polarity. Analyzing polarity signals under physiological conditions will provide a better understanding of how neurons can be induced to repolarize under pathological conditions, i.e., to regenerate their axons after central nervous system (CNS) injury.One ambitious aim in cellular biology is to unravel the molecular mechanisms driving cellular asymmetry and polarization. The polarity of neurons is particularly dramatic as neurons undergo complex morphological rearrangements to assemble into neuronal circuits and propagate signals. They start as round neuronal spheres, gradually adopting a complex morphology by forming one long axon and several shorter dendrites to eventually connect to other neurons via synapses. Neuronal compartments segregate into molecularly and functionally distinct zones. For example, signal input takes place at the postsynaptic densities where a chemical signal elicits electric postsynaptic potentials. These potentials are integrated along the dendritic tree and cell body to trigger an action potential arising at the axon hillock and propagating further along the axon. At their terminals, the electrical signal is reconverted into a chemical signal by the release of synaptic vesicles containing neurotransmitter.Neurons maintain their polarity throughout life by different intracellular mechanisms and molecular signals. During the last decade, cell biological and molecular approaches helped to discover many of the molecules and signaling mechanisms regulating neuronal polarity (Yoshimura et al. 2006; Arimura and Kaibuchi 2007; Witte and Bradke 2008). The aim of this article is to summarize the current knowledge and principles of breaking neuronal symmetry to generate functional neurons, and to discuss the future challenges in the field. The article covers two different topics: intrinsic mechanisms that govern symmetry breaking in the absence of external cues (in vitro systems) and the role of extracellular signaling in the establishment of neuronal polarity in vivo. 相似文献
18.
Qing Yang Xiao-Feng Zhang David Van Goor Ashleigh P. Dunn Callen Hyland Nelson Medeiros Paul Forscher 《Molecular biology of the cell》2013,24(19):3097-3114
Protein kinase C (PKC) can dramatically alter cell structure and motility via effects on actin filament networks. In neurons, PKC activation has been implicated in repulsive guidance responses and inhibition of axon regeneration; however, the cytoskeletal mechanisms underlying these effects are not well understood. Here we investigate the acute effects of PKC activation on actin network structure and dynamics in large Aplysia neuronal growth cones. We provide evidence of a novel two-tiered mechanism of PKC action: 1) PKC activity enhances myosin II regulatory light chain phosphorylation and C-kinase–potentiated protein phosphatase inhibitor phosphorylation. These effects are correlated with increased contractility in the central cytoplasmic domain. 2) PKC activation results in significant reduction of P-domain actin network density accompanied by Arp2/3 complex delocalization from the leading edge and increased rates of retrograde actin network flow. Our results show that PKC activation strongly affects both actin polymerization and myosin II contractility. This synergistic mode of action is relevant to understanding the pleiotropic reported effects of PKC on neuronal growth and regeneration. 相似文献
19.
Interaction of nonreceptor tyrosine-kinase Fer and p120 catenin is involved in neuronal polarization
Lee SH 《Molecules and cells》2005,20(2):256-262
The neuronal cytoskeleton is essential for establishment of neuronal polarity, but mechanisms controlling generation of polarity in the cytoskeleton are poorly understood. The nonreceptor tyrosine kinase, Fer, has been shown to bind to microtubules and to interact with several actin-regulatory proteins. Furthermore, Fer binds p120 catenin and has been shown to regulate cadherin function by modulating cadherin-beta-catenin interaction. Here we show involvement of Fer in neuronal polarization and neurite development. Fer is concentrated in growth cones together with cadherin, beta-catenin, and cortactin in stage 2 hippocampal neurons. Inhibition of Fer-p120 catenin interaction with a cell-permeable inhibitory peptide (FerP) increases neurite branching. In addition, the peptide significantly delays conversion of one of several dendrites into an axon in early stage hippocampal neurons. FerP-treated growth cones also exhibit modified localization of the microtubule and actin cytoskeleton. Together, this indicates that the Fer-p120 interaction is required for normal neuronal polarization and neurite development. 相似文献