Neurofascin assembles a specialized extracellular matrix at the axon initial segment

Action potential initiation and propagation requires clustered Na+ (voltage-gated Na+ [Nav]) channels at axon initial segments (AIS) and nodes of Ranvier. In addition to ion channels, these domains are characterized by cell adhesion molecules (CAMs; neurofascin-186 [NF-186] and neuron glia–related CAM [NrCAM]), cytoskeletal proteins (ankyrinG and βIV spectrin), and the extracellular chondroitin-sulfate proteoglycan brevican. Schwann cells initiate peripheral nervous system node formation by clustering NF-186, which then recruits ankyrinG and Nav channels. However, AIS assembly of this protein complex does not require glial contact. To determine the AIS assembly mechanism, we silenced expression of AIS proteins by RNA interference. AnkyrinG knockdown prevented AIS localization of all other AIS proteins. Loss of NF-186, NrCAM, Nav channels, or βIV spectrin did not affect other neuronal AIS proteins. However, loss of NF-186 blocked assembly of the brevican-based AIS extracellular matrix, and NF-186 overexpression caused somatodendritic brevican clustering. Thus, NF-186 assembles and links the specialized brevican-containing AIS extracellular matrix to the intracellular cytoskeleton.

• Publication year

  2007

• Venue

  Journal of Cell Biology

• Publication date

  2007-08-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/jcb.200705119PMID 17709431PMCID 2064550
• 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.

• βIV spectrin is recruited to axon initial segments and nodes of Ranvier by ankyrinG

  2007influential reference
• Ankyrin-Dependent and -Independent Mechanisms Orchestrate Axonal Compartmentalization of L1 Family Members Neurofascin and L1/Neuron–Glia Cell Adhesion Molecule

  2007cited by this paper
• Neuronal polarity: from extracellular signals to intracellular mechanisms

  2007cited by this paper
• Secreted gliomedin is a perinodal matrix component of peripheral nerves

  2007influential reference
• Properties of action-potential initiation in neocortical pyramidal cells: evidence from whole cell axon recordings.

  2007cited by this paper
• Nodes of Ranvier and axon initial segments are ankyrin G–dependent domains that assemble by distinct mechanisms

  2007cited by this paper
• Brevican-containing perineuronal nets of extracellular matrix in dissociated hippocampal primary cultures.

  2006influential reference
• Spectrins and AnkyrinB Constitute a Specialized Paranodal Cytoskeleton

  2006influential reference
• Coincident enrichment of phosphorylated IkappaBalpha, activated IKK, and phosphorylated p65 in the axon initial segment of neurons.

  2006cited by this paper
• In vivo electroporation in the embryonic mouse central nervous system

  2006cited by this paper
• Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells.

  2006cited by this paper
• Relative Contributions of Axonal and Somatic Na Channels to Action Potential Initiation in Cerebellar Purkinje Neurons

  2006cited by this paper
• Unique features of action potential initiation in cortical neurons

  2006cited by this paper
• A Common Ankyrin-G-Based Mechanism Retains KCNQ and NaV Channels at Electrically Active Domains of the Axon

  2006influential reference
• Intrinsic and extrinsic determinants of ion channel localization in neurons

  2006cited by this paper
• Site of Action Potential Initiation in Layer 5 Pyramidal Neurons

  2006cited by this paper
• Oligodendrocytes regulate formation of nodes of Ranvier via the recognition molecule OMgp.

  2006cited by this paper
• Glial regulation of the axonal membrane at nodes of Ranvier.

  2006influential reference
• Dependence of axon initial segment formation on Na+ channel expression

  2005influential reference
• Differential expression of proteoglycans at central and peripheral nodes of Ranvier

  2005cited by this paper
• Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier.

  2005cited by this paper
• Glial Membranes at the Node of Ranvier Prevent Neurite Outgrowth

  2005cited by this paper
• Neurofascins are required to establish axonal domains for saltatory conduction.

  2005influential reference
• βIV Spectrins Are Essential for Membrane Stability and the Molecular Organization of Nodes of Ranvier

  2004cited by this paper
• Does Paranode Formation and Maintenance Require Partitioning of Neurofascin 155 into Lipid Rafts?

  2004influential reference
• Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment.

  2004cited by this paper
• A Targeting Motif Involved in Sodium Channel Clustering at the Axonal Initial Segment

  2003influential reference
• Rapid method for culturing embryonic neuron–glial cell cocultures

  2003cited by this paper
• Identification of a Conserved Ankyrin-binding Motif in the Family of Sodium Channel α Subunits*

  2003influential reference
• An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting

  2003cited by this paper
• The Role of the Ankyrin-Binding Protein NrCAM in Node of Ranvier Formation

  2003influential reference
• Uncovering multiple axonal targeting pathways in hippocampal neurons

  2003cited by this paper
• Brevican-Deficient Mice Display Impaired Hippocampal CA1 Long-Term Potentiation but Show No Obvious Deficits in Learning and Memory

  2002cited by this paper
• βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier

  2002influential reference
• Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments

  2001cited by this paper
• Lecticans: organizers of the brain extracellular matrix

  2000cited by this paper
• A novel targeting signal for proximal clustering of the Kv2.1 K+ channel in hippocampal neurons.

  2000cited by this paper
• Mice Deficient for Tenascin-R Display Alterations of the Extracellular Matrix and Decreased Axonal Conduction Velocities in the CNS

  1999cited by this paper
• Restriction of 480/270-kD Ankyrin G to Axon Proximal Segments Requires Multiple Ankyrin G-specific Domains

  1998cited by this paper
• AnkyrinG Is Required for Clustering of Voltage-gated Na Channels at Axon Initial Segments and for Normal Action Potential Firing

  1998cited by this paper
• Perineuronal nets: past and present.

  1998cited by this paper
• Induction of sodium channel clustering by oligodendrocytes

  1997cited by this paper
• Tyrosine Phosphorylation at a Site Highly Conserved in the L1 Family of Cell Adhesion Molecules Abolishes Ankyrin Binding and Increases Lateral Mobility of Neurofascin

  1997cited by this paper
• Ankyrin-binding proteins related to nervous system cell adhesion molecules: candidates to provide transmembrane and intercellular connections in adult brain

  1993cited by this paper
• Culturing nerve cells

  1992cited by this paper

• Distribution of Voltage‐Gated Sodium Channels and Scaffolding Proteins on Vestibular Calyx Ending Delineates the Axon Initial Segment

  2026cites this paper
• Super‐Resolution Microscopy in Tissue Engineering

  2025cites this paper
• Sculpting excitable membranes: voltage-gated ion channel delivery and distribution

  2025influential citation
• Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice

  2025cites this paper
• Neurocan regulates axon initial segment organization and neuronal activity.

  2025cites this paper
• Potassium channel clustering: mechanisms shaping axonal excitability

  2025cites this paper
• The dynamic axon initial segment: From neuronal polarity to network homeostasis.

  2025cites this paper
• Ankyrin-G and Its Binding Partners in Neurons: Orchestrating the Molecular Structure of the Axon Initial Segment

  2025cites this paper
• The Highly Localized Interaction between Neurofascin-186 and Gliomedin Promotes Subcellular Innervation by the Chandelier Cell

  2025cites this paper
• Activity-dependent extracellular proteolytic cascade cleaves the ECM component brevican to promote structural plasticity

  2025cites this paper
• Axon Initial Segment Structure and Function in Health and Disease.

  2024cites this paper
• Astrocyte‐derived factors regulate CNS myelination

  2024cites this paper
• Activity-dependent extracellular proteolytic cascade remodels ECM to promote structural plasticity

  2024cites this paper
• Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice

  2024cites this paper
• Location of the axon initial segment assembly can be predicted from neuronal shape

  2024cites this paper
• Kinesin Regulation in the Proximal Axon is Essential for Dendrite-selective Transport

  2024influential citation
• The Nodes of Ranvier: Mechanisms of Assembly and Maintenance.

  2024cites this paper
• AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.

  2024cites this paper
• Unveiling the cell biology of hippocampal neurons with dendritic axon origin

  2024cites this paper
• Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons

  2024influential citation
• The node of Ranvier influences the in vivo axonal transport of mitochondria and signaling endosomes

  2024influential citation
• Ultrastructure of dorsal root ganglia

  2023cites this paper
• Antibody-directed extracellular proximity biotinylation reveals Contactin-1 regulates axo-axonic innervation of axon initial segments

  2023cites this paper
• The actin-spectrin submembrane scaffold restricts endocytosis along proximal axons

  2023cites this paper
• Immunoproximity biotinylation reveals the axon initial segment proteome

  2023cites this paper
• Antibody-directed extracellular proximity biotinylation reveals that Contactin-1 regulates axo-axonic innervation of axon initial segments

  2023cites this paper
• Extracellular Tau Oligomers Damage the Axon Initial Segment

  2023cites this paper
• Thalamic Neuron Resilience during Osmotic Demyelination Syndrome (ODS) Is Revealed by Primary Cilium Outgrowth and ADP-ribosylation factor-like protein 13B Labeling in Axon Initial Segment

  2023cites this paper
• Synaptic origin of early sensory-evoked oscillations in the immature thalamus.

  2023cites this paper
• CDK5/p35-Dependent Microtubule Reorganization Contributes to Homeostatic Shortening of the Axon Initial Segment

  2022cites this paper
• Chondroitin Sulphate Proteoglycan Axonal Coats in the Human Mediodorsal Thalamic Nucleus

  2022cites this paper
• The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling

  2022cites this paper
• Crystal structure of Ankyrin-G in complex with a fragment of Neurofascin reveals binding mechanisms required for integrity of the axon initial segment

  2022cites this paper
• Enzymatic Degradation of Cortical Perineuronal Nets Reverses GABAergic Interneuron Maturation

  2022cites this paper
• The axon initial segment as a source of neuropathic pain

  2022cites this paper
• Axon Initial Segments Are Required for Efficient Motor Neuron Axon Regeneration and Functional Recovery of Synapses

  2022cites this paper
• Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage

  2022cites this paper
• AnkG-Neurofascin complex structure reveals binding mechanisms required for integrity of the AIS

  2022cites this paper
• Axon-Targeting Motifs: Mechanisms and Applications of Enhancing Axonal Localisation of Transmembrane Proteins

  2022cites this paper
• Glucose increases the length and spacing of the lattice structure of the axon initial segment

  2022cites this paper
• Dynamic early clusters of nodal proteins contribute to node of Ranvier assembly during myelination of peripheral neurons

  2021cites this paper
• The role of the membrane-associated periodic skeleton in axons

  2021cites this paper
• Pathophysiological Roles of Abnormal Axon Initial Segments in Neurodevelopmental Disorders

  2021cites this paper
• Regulation of Axon Initial Segment Diameter by COUP-TFI Fine-tunes Action Potential Generation

  2021cites this paper
• Biology of Proteoglycans and Associated Glycosaminoglycans

  2021cites this paper
• Endogenously expressed Ranbp2 is not at the axon initial segment

  2021cites this paper
• Specification and Development of GABAergic Interneurons

  2021cites this paper
• Modulatory properties of extracellular matrix glycosaminoglycans and proteoglycans on neural stem cells behavior: Highlights on regenerative potential and bioactivity.

  2021cites this paper
• Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K+ channels

  2021cites this paper
• Myelination defects in the medial prefrontal cortex of Fkbp5 knockout mice

  2021cites this paper
• Diversity of Axonal and Dendritic Contributions to Neuronal Output

  2020cites this paper
• Whole-Cell Photobleaching Reveals Time-Dependent Compartmentalization of Soluble Proteins by the Axon Initial Segment

  2020cites this paper
• COUP-TFI regulates diameter of the axon initial segment in the mammalian neocortex

  2020cites this paper
• Mechanisms of node of Ranvier assembly

  2020cites this paper
• Calcineurin Signaling Mediates Disruption of the Axon Initial Segment Cytoskeleton after Injury

  2020cites this paper
• New Insights into ADAMTS Metalloproteases in the Central Nervous System

  2020cites this paper
• Nodes of Ranvier during development and repair in the CNS

  2020cites this paper
• Mapping axon initial segment structure and function by multiplexed proximity biotinylation

  2020cites this paper
• Structure and function of myelinated axons

  2020cites this paper
• Molecular characterization and distribution of the voltage-gated sodium channel, Para, in the brain of the grasshopper and vinegar fly

  2020cites this paper
• Ecm29-mediated proteasomal distribution modulates excitatory GABA responses in the developing brain

  2020cites this paper
• Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings

  2019cites this paper
• SiRNA-mediated ankyrin-G silence modulates the expression of voltage-gated Na channels in murine hippocampal HT22 cells

  2019cites this paper
• Maturation Dynamics of the Axon Initial Segment (AIS) of Newborn Dentate Granule Cells in Young Adult C57BL/6J Mice

  2019cites this paper
• Ankyrin-G induces nucleoporin Nup358 to associate with the axon initial segment of neurons

  2019influential citation
• Learning Induces Transient Upregulation of Brevican in the Auditory Cortex during Consolidation of Long-Term Memories

  2019cites this paper
• Axo-axonic Innervation of Neocortical Pyramidal Neurons by GABAergic Chandelier Cells Requires AnkyrinG-Associated L1CAM.

  2019cites this paper
• Feedback-Driven Assembly of the Axon Initial Segment

  2019cites this paper
• Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model

  2019cites this paper
• The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function

  2019cites this paper
• Under the ECM Dome: The Physiological Role of the Perinodal Extracellular Matrix as an Ion Diffusion Barrier.

  2019cites this paper
• Loss of Neurofascin-186 Disrupts Alignment of AnkyrinG Relative to Its Binding Partners in the Axon Initial Segment

  2019cites this paper
• P2Y1 Purinergic Receptor Modulate Axon Initial Segment Initial Development

  2019cites this paper
• Locally Activating TrkB Receptor Generates Actin Waves and Specifies Axonal Fate.

  2019cites this paper
• The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest

  2019cites this paper
• NuMA1 promotes axon initial segment assembly through inhibition of endocytosis

  2019cites this paper
• Nodal Dynamics after In Vivo Rescue of βIV Spectrin Expression

  2019cites this paper
• Crosstalk between glia, extracellular matrix and neurons.

  2018cites this paper
• Localized Myosin II Activity Regulates Assembly and Plasticity of the Axon Initial Segment.

  2018cites this paper
• Neurocan Inhibits Semaphorin 3F Induced Dendritic Spine Remodeling Through NrCAM in Cortical Neurons

  2018cites this paper
• Sound encoding in mutant mice with disrupted action potential generation

  2018cites this paper
• Roles of Basigin in structure and function of the Drosophila peripheral nerve

  2018cites this paper
• Rbfox Splicing Factors Promote Neuronal Maturation and Axon Initial Segment Assembly.

  2018cites this paper
• The Adhesion-GPCR BAI1 Promotes Excitatory Synaptogenesis by Coordinating Bidirectional Trans-synaptic Signaling

  2018cites this paper
• The Axon Initial Segment is the Dominant Contributor to the Neuron's Extracellular Electrical Potential Landscape

  2018cites this paper
• The intriguing nature of dorsal root ganglion neurons: Linking structure with polarity and function

  2018cites this paper
• βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy.

  2018cites this paper
• The Axon Initial Segment: An Updated Viewpoint

  2018influential citation
• The axon initial segment drives the neuron’s extracellular action potential

  2018cites this paper
• Axon outgrowth and neuronal differentiation defects after a-SMN and FL-SMN silencing in primary hippocampal cultures

  2018cites this paper
• Axon initial segments: structure, function, and disease

  2018cites this paper
• Cell-Permeant Large Stokes Shift Dyes for Transfection-Free Multicolor Nanoscopy.

  2017cites this paper
• αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function

  2017cites this paper
• The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders.

  2017cites this paper
• The nano-architecture of the axonal cytoskeleton

  2017cites this paper
• Altered Axon Initial Segment Structure and Function In Inflammatory Disease

  2017cites this paper
• The Segregated Expression of Voltage-Gated Potassium and Sodium Channels in Neuronal Membranes: Functional Implications and Regulatory Mechanisms

  2017cites this paper
• Maternal Different Degrees of Iodine Deficiency during Pregnant and Lactation Impair the Development of Cerebellar Pinceau in Offspring

  2017influential citation
• MAP2 Defines a Pre-axonal Filtering Zone to Regulate KIF1- versus KIF5-Dependent Cargo Transport in Sensory Neurons.

  2017cites this paper
• Neocortical Chandelier Cells Developmentally Shape Axonal Arbors through Reorganization but Establish Subcellular Synapse Specificity without Refinement

  2017cites this paper