Small Nodes of Ranvier From Peripheral Nerves of Mice Reconstructed by Electron Tomography

The node of Ranvier is a complex structure found along myelinated nerves of vertebrate animals. Specific membrane, cytoskeletal, junctional, extracellular matrix proteins and organelles interact to maintain and regulate associated ion movements between spaces in the nodal complex, potentially influencing response variation during repetitive activations or metabolic stress. Understanding and building high resolution three dimensional (3D) structures of the node of Ranvier, including localization of specific macromolecules, is crucial to a better understanding of the relationship between its structure and function and the macromolecular basis for impaired conduction in disease. Using serial section electron tomographic methods, we have constructed accurate 3D models of the nodal complex from mouse spinal roots with resolution better than 7.5 nm. These reconstructed volumes contain 75‐80% of the thickness of the nodal region. We also directly imaged the glial axonal junctions that serve to anchor the terminal loops of the myelin lamellae to the axolemma. We created a model of an intact node of Ranvier by truncating the volume at its midpoint in Z, duplicating the remaining volume and then merging the new half volume with mirror symmetry about the Z-axis. We added to this model the distribution and number of Na + channels on this reconstruction using tools associated with the MCell simulation program environment. The model created provides accurate structural descriptions of the membrane compartments, external spaces, and formed

[1]  C H Berthold,et al.  Postnatal development of feline paranodal myelin-sheath segments. I. Light microscopy. , 1968, Acta Societatis Medicorum Upsaliensis.

[2]  H. Webster,et al.  THE GEOMETRY OF PERIPHERAL MYELIN SHEATHS DURING THEIR FORMATION AND GROWTH IN RAT SCIATIC NERVES , 1971, The Journal of cell biology.

[3]  K. Akert,et al.  Specialized paranodal and interparanodal glial-axonal junctions in the peripheral and central nervous system: a freeze-etching study. , 1973, Brain research.

[4]  H. Webster,et al.  The relationships between interphase Schwann cells and axons before myelination: a quantitative electron microscopic study. , 1973, Developmental biology.

[5]  Ritchie Jm,et al.  The binding of labelled saxitoxin to normal and denervated muscle [proceedings]. , 1976 .

[6]  J. Rosenbluth,et al.  Intramembranous particle distribution at the node of Ranvier and adjacent axolemma in myelinated axons of the frog brain , 1976, Journal of neurocytology.

[7]  J. Wood,et al.  Immunocytochemical localization of the sodium, potassium activated ATPase in knifefish brain , 1977, Journal of neurocytology.

[8]  J. M. Ritchie,et al.  Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[9]  K. Akert,et al.  Intramembranous particles at the nodes of Ranvier of the cat spinal cord: A morphometric study , 1978, Brain Research.

[10]  M H Ellisman,et al.  Molecular specializations of the axon membrane at nodes of Ranvier are not dependent upon myelination , 1979, Journal of neurocytology.

[11]  M H Ellisman,et al.  Development of axonal membrane specializations defines nodes of Ranvier and precedes Schwann cell myelin elaboration. , 1980, Developmental biology.

[12]  M H Ellisman,et al.  Rows of dimeric-particles within the axolemma and juxtaposed particles within glia, incorporated into a new model for the paranodal glial- axonal junction at the node of Ranvier , 1980, The Journal of cell biology.

[13]  M H Ellisman,et al.  Microtrabecular structure of the axoplasmic matrix: visualization of cross-linking structures and their distribution , 1980, The Journal of cell biology.

[14]  Mark H. Ellisman,et al.  Myelination-dependent axonal membrane specializations demonstrated in insufficiently myelinated nerves of the dystrophic mouse , 1981, Brain Research.

[15]  Robert E. Foster,et al.  Rat optic nerve: Freeze-fracture studies during development of myelinated axons , 1982, Brain Research.

[16]  M H Ellisman,et al.  Immunocytochemical localization of sodium channel distributions in the excitable membranes of Electrophorus electricus. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M H Ellisman,et al.  Electron microscopic visualization of the tetrodotoxin-binding protein from Electrophorus electricus. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Rydmark,et al.  Axon diameter and myelin sheath thickness in nerve fibres of the ventral spinal root of the seventh lumbar nerve of the adult and developing cat. , 1983, Journal of anatomy.

[19]  M H Ellisman,et al.  The voltage-regulated sodium channel from the electroplax of Electrophorus electricus. , 1983, Cold Spring Harbor symposia on quantitative biology.

[20]  B. Hille Ionic channels of excitable membranes , 2001 .

[21]  A. Steck,et al.  Impulse Conduction Regulates Myelin Basic Protein Phosphorylation in Rat Optic Nerve , 1984, Journal of neurochemistry.

[22]  Clayton A. Wiley,et al.  STRUCTURE AND FUNCTION OF THE CYTOSKELETON AND ENDOMEMBRANE SYSTEMS AT THE NODE OF RANVIER , 1984 .

[23]  M H Ellisman,et al.  Localization of sodium/potassium adenosine triphosphatase in multiple cell types of the murine nervous system with antibodies raised against the enzyme from kidney , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  A Grinvald,et al.  Ca2+- and K+-dependent communication between central nervous system myelinated axons and oligodendrocytes revealed by voltage-sensitive dyes. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[25]  W. Endres,et al.  Changes in extracellular pH during electrical stimulation of isolated rat vagus nerve , 1986, Neuroscience Letters.

[26]  M H Ellisman,et al.  Alterations in the ultrastructure of peripheral nodes of Ranvier associated with repetitive action potential propagation , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  A. Grinvald,et al.  Activity-dependent calcium transients in central nervous system myelinated axons revealed by the calcium indicator Fura-2. , 1987, Biophysical journal.

[28]  L. R. Carley,et al.  Comparison of the after‐effects of impulse conduction on threshold at nodes of Ranvier along single frog sciatic axons. , 1987, The Journal of physiology.

[29]  H. Moor Theory and practice of high pressure freezing. , 1987 .

[30]  Mark H Ellisman,et al.  Diagnostic levels of ultrasound may disrupt myelination , 1987, Experimental Neurology.

[31]  Bruce D. Trapp,et al.  Co-localization of the myelin-associated glycoprotein and the microfilament components, F-actin and spectrin, in Schwann cells of myelinated nerve fibres , 1989, Journal of neurocytology.

[32]  R. Dahl,et al.  High-pressure freezing for the preservation of biological structure: theory and practice. , 1989, Journal of electron microscopy technique.

[33]  Peter Shrager,et al.  Sodium channels in single demyelinated mammalian axons , 1989, Brain Research.

[34]  J Frank,et al.  Image analysis of single macromolecules. , 1989, Electron microscopy reviews.

[35]  M H Ellisman,et al.  Three-dimensional fine structure of cytoskeletal-membrane interactions at nodes of Ranvier , 1991, Journal of neurocytology.

[36]  T. Bartol,et al.  Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction. , 1991, Biophysical journal.

[37]  S. Chiu,et al.  Functions and distribution of voltage‐gated sodium and potassium channels in mammalian schwann cells , 1991, Glia.

[38]  T A Gennarelli,et al.  Focal axonal injury: the early axonal response to stretch , 1991, Journal of neurocytology.

[39]  B. Barres,et al.  New roles for glia , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[40]  Sima Aa,et al.  Diabetic neuropathy--the presence and future of a common but silent disorder. , 1993 .

[41]  J. M. Ritchie,et al.  Molecular dissection of the myelinated axon , 1993, Annals of neurology.

[42]  K. Fischbeck,et al.  Connexin mutations in X-linked Charcot-Marie-Tooth disease. , 1993, Science.

[43]  J. Clark,et al.  The influence of nodal constriction on conduction velocity in myelinated nerve fibers. , 1993, Neuroreport.

[44]  Peter J. Brophy,et al.  Periaxin, a novel protein of myelinating schwann cells with a possible role in axonal ensheathment , 1994, Neuron.

[45]  J R Kremer,et al.  HVEM tomography of the trans-Golgi network: structural insights and identification of a lace-like vesicle coat , 1994, The Journal of cell biology.

[46]  Mark H. Ellisman,et al.  Serial Section Electron Tomography: A Method for Three-Dimensional Reconstruction of Large Structures , 1994, NeuroImage.

[47]  J Frank,et al.  The internal compartmentation of rat‐liver mitochondria: Tomographic study using the high‐voltage transmission electron microscope , 1994, Microscopy research and technique.

[48]  M. Rydmark,et al.  Axonal constriction at Ranvier's node increases during development , 1995, Neuroscience Letters.

[49]  D. Sherman,et al.  Periaxin expression in myelinating Schwann cells: modulation by axon-glial interactions and polarized localization during development. , 1995, Development.

[50]  M H Ellisman,et al.  Axonal activation-induced calcium transients in myelinating Schwann cells, sources, and mechanisms , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  D. Paul,et al.  New functions for gap junctions. , 1995, Current opinion in cell biology.

[52]  M H Ellisman,et al.  Differential distribution of closely related potassium channels in rat Schwann cells , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[53]  V. Ionasescu,et al.  Charcot–marie–tooth neuropathies: From clinical description to molecular genetics , 1995, Muscle & nerve.

[54]  D. Sherman,et al.  Novel E-cadherin-mediated adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions [published erratum appears in J Cell Biol 1995 Jun;129(6):1721] , 1995, The Journal of cell biology.

[55]  J. Frank,et al.  Double-tilt electron tomography. , 1995, Ultramicroscopy.

[56]  M. Peifer,et al.  Not just glue: cell-cell junctions as cellular signaling centers. , 1995, Current opinion in genetics & development.

[57]  C H Berthold,et al.  Development of nodes of Ranvier in feline nerves: An ultrasturctural presentation , 1996, Microscopy research and technique.

[58]  J R Kremer,et al.  Computer visualization of three-dimensional image data using IMOD. , 1996, Journal of structural biology.

[59]  J W Griffin,et al.  Early nodal changes in the acute motor axonal neuropathy pattern of the Guillain-Barré syndrome , 1996, Journal of neurocytology.

[60]  Melitta Schachner,et al.  The Clustering of Axonal Sodium Channels during Development of the Peripheral Nervous System , 1996, The Journal of Neuroscience.

[61]  A. Sima,et al.  An orderly development of paranodal axoglial junctions and bracelets of Nageotte in the rat sural nerve. , 1996, Brain research. Developmental brain research.

[62]  M H Ellisman,et al.  Inwardly rectifying K+ channels that may participate in K+ buffering are localized in microvilli of Schwann cells , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[63]  G A Perkins,et al.  Electron tomography of large, multicomponent biological structures. , 1997, Journal of structural biology.

[64]  V. Bennett,et al.  Morphogenesis of the Node of Ranvier: Co-Clusters of Ankyrin and Ankyrin-Binding Integral Proteins Define Early Developmental Intermediates , 1997, The Journal of Neuroscience.

[65]  S J Young,et al.  Electron tomography of neuronal mitochondria: three-dimensional structure and organization of cristae and membrane contacts. , 1997, Journal of structural biology.

[66]  D. Mastronarde Dual-axis tomography: an approach with alignment methods that preserve resolution. , 1997, Journal of structural biology.

[67]  E. Shimoni,et al.  On optimizing high‐pressure freezing: from heat transfer theory to a new microbiopsy device , 1998, Journal of microscopy.

[68]  P. Shrager,et al.  Ion channel redistribution and function during development of the myelinated axon. , 1998, Journal of neurobiology.

[69]  Mark H. Ellisman,et al.  Modification of Postsynaptic Densities after Transient Cerebral Ischemia: A Quantitative and Three-Dimensional Ultrastructural Study , 1999, The Journal of Neuroscience.

[70]  M H Ellisman,et al.  Synaptic Vesicle Populations in Saccular Hair Cells Reconstructed by Electron Tomography , 1999, The Journal of Neuroscience.

[71]  M. Itoh,et al.  Structural and signalling molecules come together at tight junctions. , 1999, Current opinion in cell biology.

[72]  K. Fischbeck,et al.  The role of the gap junction protein connexin32 in the pathogenesis of X-linked Charcot-Marie-Tooth disease. , 1999, Novartis Foundation symposium.

[73]  K. McDonald,et al.  High-pressure freezing for preservation of high resolution fine structure and antigenicity for immunolabeling. , 1999, Methods in molecular biology.

[74]  Jean-Antoine Girault,et al.  Axo-Glial Interactions Regulate the Localization of Axonal Paranodal Proteins , 1999, The Journal of cell biology.

[75]  R. Harris-Warrick,et al.  Identification and localization of Ca2+‐activated K+ channels in rat sciatic nerve , 1999 .

[76]  C. Croce,et al.  huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[77]  A S Frangakis,et al.  Cryo-electron tomography of neurospora mitochondria. , 2000, Journal of structural biology.

[78]  T. Bartol,et al.  Monte Carlo Methods for Simulating Realistic Synaptic Microphysiology Using MCell , 2000 .

[79]  Karl Matter,et al.  The tight junction protein ZO‐1 and an interacting transcription factor regulate ErbB‐2 expression , 2000, The EMBO journal.

[80]  D. Sherman,et al.  An Oligodendrocyte Cell Adhesion Molecule at the Site of Assembly of the Paranodal Axo-Glial Junction , 2000, The Journal of cell biology.

[81]  Melitta Schachner,et al.  Contactin Associates with Na+ Channels and Increases Their Functional Expression , 2001, The Journal of Neuroscience.

[82]  J. Levine,et al.  Deposition of the NG2 Proteoglycan at Nodes of Ranvier in the Peripheral Nervous System , 2001, The Journal of Neuroscience.

[83]  J. Meuleman,et al.  Caspr1/Paranodin/Neurexin IV is most likely not a common disease-causing gene for inherited peripheral neuropathies , 2001, Neuroreport.

[84]  Elior Peles,et al.  Contactin Orchestrates Assembly of the Septate-like Junctions at the Paranode in Myelinated Peripheral Nerve , 2001, Neuron.

[85]  A. Bretscher,et al.  Nodes of Ranvier form in association with ezrin-radixin-moesin (ERM)-positive Schwann cell processes. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[86]  P. Crino,et al.  Ezrin, radixin, and moesin are components of Schwann cell microvilli , 2001, Journal of neuroscience research.

[87]  D. Mastronarde,et al.  Organellar relationships in the Golgi region of the pancreatic beta cell line, HIT-T15, visualized by high resolution electron tomography , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[88]  Arne Stoschek,et al.  The architecture of active zone material at the frog's neuromuscular junction , 2001, Nature.

[89]  E. Peles,et al.  Localization of Caspr2 in Myelinated Nerves Depends on Axon–Glia Interactions and the Generation of Barriers along the Axon , 2001, The Journal of Neuroscience.

[90]  R. Martini,et al.  The effect of myelinating Schwann cells on axons , 2001, Muscle & nerve.

[91]  M L Hines,et al.  Neuron: A Tool for Neuroscientists , 2001, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[92]  F. Alvarez-Leefmans,et al.  Immunolocalization of the Na+–K+–2Cl− cotransporter in peripheral nervous tissue of vertebrates , 2001, Neuroscience.

[93]  Hugo J. Bellen,et al.  Axon-Glia Interactions and the Domain Organization of Myelinated Axons Requires Neurexin IV/Caspr/Paranodin , 2001, Neuron.

[94]  Jean-Antoine Girault,et al.  Development of nodes of Ranvier , 2002, Current Opinion in Neurobiology.

[95]  Terrence J Sejnowski,et al.  A Monte Carlo model reveals independent signaling at central glutamatergic synapses. , 2002, Biophysical journal.

[96]  Bertram Ludäscher,et al.  A cell-centered database for electron tomographic data. , 2002, Journal of structural biology.

[97]  Mark H Ellisman,et al.  Ultrastructure of a Somatic Spine Mat for Nicotinic Signaling in Neurons , 2002, The Journal of Neuroscience.

[98]  Bruce M Altevogt,et al.  Connexin29 Is Uniquely Distributed within Myelinating Glial Cells of the Central and Peripheral Nervous Systems , 2002, The Journal of Neuroscience.

[99]  W. Baumeister,et al.  Macromolecular Architecture in Eukaryotic Cells Visualized by Cryoelectron Tomography , 2002, Science.

[100]  Stephen Lambert,et al.  Local ERM activation and dynamic growth cones at Schwann cell tips implicated in efficient formation of nodes of Ranvier , 2003, The Journal of cell biology.

[101]  J. Salzer,et al.  Polarized Domains of Myelinated Axons , 2003, Neuron.

[102]  J. Salzer,et al.  Paranodal Interactions Regulate Expression of Sodium Channel Subtypes and Provide a Diffusion Barrier for the Node of Ranvier , 2003, The Journal of Neuroscience.

[103]  Mark Ellisman,et al.  e-Neuroscience: challenges and triumphs in integrating distributed data from molecules to brains , 2004, Nature Neuroscience.

[104]  Simone Santini,et al.  The cell-centered database , 2007, Neuroinformatics.