The axonal cytoskeleton: from organization to function

The axon is the single long fiber that extends from the neuron and transmits electrical signals away from the cell body. The neuronal cytoskeleton, composed of microtubules (MTs), actin filaments and neurofilaments, is not only required for axon formation and axonal transport but also provides the structural basis for several specialized axonal structures, such as the axon initial segment (AIS) and presynaptic boutons. Emerging evidence suggest that the unique cytoskeleton organization in the axon is essential for its structure and integrity. In addition, the increasing number of neurodevelopmental and neurodegenerative diseases linked to defect in actin- and microtubule-dependent processes emphasizes the importance of a properly regulated cytoskeleton for normal axonal functioning. Here, we provide an overview of the current understanding of actin and microtubule organization within the axon and discuss models for the functional role of the cytoskeleton at specialized axonal structures.

• Publication year

  2015

• Venue

  Frontiers in Molecular Neuroscience

• Publication date

  2015-08-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fnmol.2015.00044PMID 26321907PMCID 4536388
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Actin Migration Driven by Directional Assembly and Disassembly of Membrane-Anchored Actin Filaments.

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• Miro's N-Terminal GTPase Domain Is Required for Transport of Mitochondria into Axons and Dendrites

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• Characterizing KIF16B in Neurons Reveals a Novel Intramolecular “Stalk Inhibition” Mechanism That Regulates Its Capacity to Potentiate the Selective Somatodendritic Localization of Early Endosomes

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• Kinesin-1–powered microtubule sliding initiates axonal regeneration in Drosophila cultured neurons

  2015influential reference
• Hierarchical microtubule organization controls axon caliber and transport and determines synaptic structure and stability.

  2015cited by this paper
• A dynamic formin-dependent deep F-actin network in axons

  2015influential reference
• Molecular Remodeling of the Presynaptic Active Zone of Drosophila Photoreceptors via Activity-Dependent Feedback.

  2015cited by this paper
• ADF/Cofilin Controls Synaptic Actin Dynamics and Regulates Synaptic Vesicle Mobilization and Exocytosis.

  2015cited by this paper
• Systemic administration of epothilone B promotes axon regeneration after spinal cord injury

  2015cited by this paper
• Relevance of presynaptic actin dynamics for synapse function and mouse behavior.

  2015influential reference
• X‐ray and Cryo‐EM structures reveal mutual conformational changes of Kinesin and GTP‐state microtubules upon binding

  2015cited by this paper
• Nerve growth factor promotes reorganization of the axonal microtubule array at sites of axon collateral branching

  2015influential reference
• Dynamic microtubules drive circuit rewiring in the absence of neurite remodeling.

  2015cited by this paper
• Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms

  2015cited by this paper
• Microtubule Plus‐End‐Tracking Proteins

  2015cited by this paper
• Synaptic democracy and vesicular transport in axons.

  2015cited by this paper
• STED nanoscopy reveals the ubiquity of subcortical cytoskeleton periodicity in living neurons.

  2015cited by this paper
• Piccolo Directs Activity Dependent F-Actin Assembly from Presynaptic Active Zones via Daam1

  2015cited by this paper
• Post-translational modifications of tubulin: pathways to functional diversity of microtubules.

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• Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

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• Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment

  2015cited by this paper
• Extracellular architecture of the SYG-1/SYG-2 adhesion complex instructs synaptogenesis.

  2014cited by this paper
• Macromolecular complexes at active zones: integrated nano-machineries for neurotransmitter release

  2014cited by this paper
• Microtubule dynamics in axon guidance

  2014cited by this paper
• Local F-actin network links synapse formation and axon branching.

  2014influential reference
• Axon and dendritic trafficking.

  2014cited by this paper
• Extended phenotypic spectrum of KIF5A mutations

  2014cited by this paper
• Neuronal cytoskeleton in synaptic plasticity and regeneration

  2014cited by this paper
• Lost after translation: missorting of Tau protein and consequences for Alzheimer disease.

  2014cited by this paper
• Axon initial segments: diverse and dynamic neuronal compartments.

  2014cited by this paper
• Microtubule orientation and spacing within bundles is critical for long‐range kinesin‐1 motility

  2014cited by this paper
• Biophysical challenges to axonal transport: motor-cargo deficiencies and neurodegeneration.

  2014cited by this paper
• Fluorogenic probes for live-cell imaging of the cytoskeleton

  2014cited by this paper
• CaV2.2 channel cell surface expression is regulated by the light chain 1 (LC1) of the microtubule-associated protein B (MAP1B) via UBE2L3-mediated ubiquitination and degradation

  2014cited by this paper
• Kinesin superfamily proteins and the regulation of microtubule dynamics in morphogenesis

  2014cited by this paper
• Actin dynamics in growth cone motility and navigation

  2014cited by this paper
• No Pasaran! Role of the axon initial segment in the regulation of protein transport and the maintenance of axonal identity.

  2014cited by this paper
• A Presynaptic Role of Microtubule-Associated Protein 1/Futsch in Drosophila: Regulation of Active Zone Number and Neurotransmitter Release

  2014influential reference
• Axonal transport: cargo-specific mechanisms of motility and regulation.

  2014cited by this paper
• Selective Microtubule-Based Transport of Dendritic Membrane Proteins Arises in Concert with Axon Specification

  2014cited by this paper
• Cytoskeletal and signaling mechanisms of neurite formation

  2014cited by this paper
• Microtubules and neurodevelopmental disease: the movers and the makers.

  2014cited by this paper
• Unique Function of Kinesin Kif5A in Localization of Mitochondria in Axons

  2014cited by this paper
• Faculty Opinions recommendation of Initial neurite outgrowth in Drosophila neurons is driven by kinesin-powered microtubule sliding.

  2014cited by this paper
• Terminal Axonal Arborization and Synaptic Bouton Formation Critically Rely on Abp1 and the Arp2/3 Complex

  2014cited by this paper
• Axonal transport: how high microtubule density can compensate for boundary effects in small-caliber axons.

  2014cited by this paper
• Axon initial segment cytoskeleton comprises a multiprotein submembranous coat containing sparse actin filaments

  2014influential reference
• Dynamic mechanisms of neuroligin-dependent presynaptic terminal assembly in living cortical neurons

  2014cited by this paper
• Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.

  2014cited by this paper
• Integrin signalling and traffic during axon growth and regeneration.

  2014cited by this paper
• Microtubule-based transport – basic mechanisms, traffic rules and role in neurological pathogenesis

  2013cited by this paper
• Motile axonal mitochondria contribute to the variability of presynaptic strength.

  2013cited by this paper
• Actin, Spectrin, and Associated Proteins Form a Periodic Cytoskeletal Structure in Axons

  2013cited by this paper
• Cellular and molecular mechanisms underlying presynapse formation

  2013cited by this paper
• The changing scene of amyotrophic lateral sclerosis

  2013cited by this paper
• β‐Tubulin mutations that cause severe neuropathies disrupt axonal transport

  2013cited by this paper
• Axonal transport deficits and neurodegenerative diseases

  2013cited by this paper
• MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells

  2013cited by this paper
• Spartin regulates synaptic growth and neuronal survival by inhibiting BMP-mediated microtubule stabilization.

  2013cited by this paper
• The balance between capture and dissociation of presynaptic proteins controls the spatial distribution of synapses.

  2013cited by this paper
• Kinesin-1 and mitochondrial motility control by discrimination of structurally equivalent but distinct subdomains in Ran-GTP-binding domains of Ran-binding protein 2

  2013cited by this paper
• The actin cytoskeleton in presynaptic assembly

  2013influential reference
• JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors

  2013cited by this paper
• TRAK/Milton motor-adaptor proteins steer mitochondrial trafficking to axons and dendrites.

  2013cited by this paper
• Spectrin- and ankyrin-based membrane domains and the evolution of vertebrates.

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• Branch management: mechanisms of axon branching in the developing vertebrate CNS

  2013cited by this paper
• CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor.

  2013cited by this paper
• Growth cone travel in space and time: the cellular ensemble of cytoskeleton, adhesion, and membrane.

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• Neurofilaments at a glance

  2012cited by this paper
• NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins

  2012cited by this paper
• Growth Cone Travel in Space and Time : the Cellular Ensemble of Cytoskeleton , Adhesion , and Membrane

  2012cited by this paper
• Networks of polarized actin filaments in the axon initial segment provide a mechanism for sorting axonal and dendritic proteins.

  2012cited by this paper
• The presynaptic active zone.

  2012cited by this paper
• Neuropeptide delivery to synapses by long-range vesicle circulation and sporadic capture.

  2012cited by this paper
• Differential trafficking of transport vesicles contributes to the localization of dendritic proteins.

  2012cited by this paper
• ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain.

  2012cited by this paper
• Formation of Golgi-Derived Active Zone Precursor Vesicles

  2012cited by this paper
• Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment.

  2012influential reference
• Molecular organization and plasticity of the cytomatrix at the active zone.

  2012cited by this paper
• Molecular basis of axonal dysfunction and traffic impairments in CMT.

  2012cited by this paper
• Preferential binding of a kinesin-1 motor to GTP-tubulin–rich microtubules underlies polarized vesicle transport

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• The Structure of the Kinesin-1 Motor-Tail Complex Reveals the Mechanism of Autoinhibition

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• Regulation of microtubule dynamics by kinesins.

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• End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

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• Piccolo Regulates the Dynamic Assembly of Presynaptic F-Actin

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• The cytoskeletal and signaling mechanisms of axon collateral branching

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• Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration After Spinal Cord Injury

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• KIF1A is the primary anterograde motor protein required for the axonal transport of dense-core vesicles in cultured hippocampal neurons.

  2011influential reference
• Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations.

  2011cited by this paper
• Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions

  2011cited by this paper
• Mechanisms and molecules of neuronal wiring: a primer.

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• Neuronal polarization: The cytoskeleton leads the way

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• Proteomics, Ultrastructure, and Physiology of Hippocampal Synapses in a Fragile X Syndrome Mouse Model Reveal Presynaptic Phenotype*

  2011cited by this paper
• Actin and Diseases of the Nervous System.

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• KLP6: a newly identified kinesin that regulates the morphology and transport of mitochondria in neuronal cells

  2011cited by this paper
• Coordinated trafficking of synaptic vesicle and active zone proteins prior to synapse formation

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• Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons*

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• Which way to go? Cytoskeletal organization and polarized transport in neurons.

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• The actin nucleating Arp2/3 complex contributes to the formation of axonal filopodia and branches through the regulation of actin patch precursors to filopodia

  2011cited by this paper
• Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease.

  2010influential reference

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• The dynamic axon initial segment: From neuronal polarity to network homeostasis.

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• Altered cytoskeleton dynamics in patient-derived iPSC-based model of PCDH19 clustering epilepsy

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• Neuronal ageing is promoted by the decay of the microtubule cytoskeleton

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• KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons

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• Neuronal activity inhibits mitochondrial transport only in synaptically connected segments of the axon

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• Cytoskeleton dysfunction of motor neuron in spinal muscular atrophy

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• KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.

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• Unveiling biomarker detection in Alzheimer’s disease: a computational approach to microarray analysis

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• Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients

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• Neuronal activity inhibits axonal mitochondrial transport in a region-specific manner

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• Characterization of transcriptional profiles associated with stress-induced neuronal activation in Arc-GFP mice

  2024cites this paper
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• A centronuclear myopathy‐causing mutation in dynamin‐2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease

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• Doxycycline inhibits dopaminergic neurodegeneration through upregulation of axonal and synaptic proteins

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  2022cites this paper
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• Protocadherins at the Crossroad of Signaling Pathways

  2020cites this paper
• Axonal cytomechanics in neuronal development

  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
• Optical Manipulation of F-Actin with Photoswitchable Small Molecules.

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• Axonal cytomechanics in neuronal development

  2020cites this paper
• Alternative splicing programming of axon formation

  2020cites this paper
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  2020cites this paper
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  2018cites this paper
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