Role of axoglial CAMs in the organization of myelinated axons

Summary

Principal Investigator: Elior Peles
Abstract: DESCRIPTION (provided by applicant): The myelin sheath covers the axon in segments that are separated by the nodes of Ranvier. In the underlying axons Na+ channels are clustered at the nodes of Ranvier, separated by a specialized axoglial paranodal junction (PNJ) from K+ channels that are found at the nearby juxtaparanodal region (JXP). This organization is essential for the saltatory movement of the nerve impulses, and its disturbance results in pathophysiological changes often seen in demyelinating human disorders. In the peripheral nervous system (PNS), myelinating Schwann cells regulate this precise organization of the axonal membrane through unknown mechanisms. We have previously identified several cell adhesion molecules (CAMs), including gliomedin, Caspr, Caspr2, and Necl4, which mediate axoglial contact at specific sites along the longitudinal axis of the myelin unit. These CAMs play important roles in the organization of myelinated axons: gliomedin cluster Na+ channels at nodes, Caspr is involved in the generation of a membrane barrier at the PNJ that restricts the distribution of Na+ and K+ channels to the nodes and JXP, respectively, Caspr2 serves as a scaffold that maintains K+ channels at the JXP, and Necl proteins organize the internodal membrane. The objective of the proposed research is to study the molecular mechanisms underlying the function of these axoglial CAMs in the generation of functional domains along myelinated axons. First, complementation experiments will be carried out using myelinating Schwann cells/neuron cultures isolated from gldn-/- mice to determine how the channels clustering activity of gliomedin is being regulated. Secondly, a transgenic rescue approach will be taken to examine the hypothesis that the PNJ restricts the distribution of Na+ channels to the nodal gap by forming a membrane barrier, which depends on the presence of the axonal cytoskeleton. Third, a similar in vivo approach will be taken in order to examine the mode of interaction between Caspr2 and TAG-1 and to reveal the underlying mechanisms by which these molecules recruit and retain Kv1 channels at the JXP. Finally, we will study the role of Necl proteins in the organization of myelinated axons by analyzing the morphology and the molecular organization of peripheral nerves of mutant mice lacking Necl4, as well as mice lacking the cytoskeletal linker protein 4.1G, which colocalizes and associates with Necl4 in myelinating Schwann cells. Altogether, the proposed experiments will provide important information about the coordinated differentiation of axons and myelin-forming cells, which allow myelinated fibers to maximize their conduction velocity. Better understanding these mechanisms may thus lead to new routes to the restoration of function in demyelinated axons and may prove useful in the design of therapeutical strategies for demyelinating disorders. PUBLIC HEALTH RELEVANCE: A functional nervous system requires the precise localization of ion channels at distinct membrane domains, where they are optimally positioned for their function. How such domains are being generated and maintained is of particular importance for our understanding of the pathological mechanisms operating in demyelinated diseases, in which reorganization of the axonal membrane and the redistribution of ion channels affects the physiological properties of the nerve fibers. Uncovering the mechanisms by which myelinating glial cells control the clustering of ion channels along myelinated axons is highly significant given the prevalence of neurodegenerating diseases that result from demyelination or alteration in myelin, such as multiple sclerosis and a number of inherited neuropathies. Our studies on the generation of functional myelinated nerves may lead to new routes to the restoration of function of demyelinated nerves.
Funding Period: 2004-12-01 - 2015-12-31
more information: NIH RePORT

Top Publications

  1. pmc Essential function of protein 4.1G in targeting of membrane protein palmitoylated 6 into Schmidt-Lanterman incisures in myelinated nerves
    Nobuo Terada
    Department of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo City, Yamanashi, Japan
    Mol Cell Biol 32:199-205. 2012
  2. pmc The cytoskeletal adapter protein 4.1G organizes the internodes in peripheral myelinated nerves
    Aleksandra Ivanovic
    Department of Molecular Neurobiology and 2 Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D 37075 Gottingen, Germany
    J Cell Biol 196:337-44. 2012
  3. ncbi Dependence of paranodal junctional gap width on transverse bands
    Jack Rosenbluth
    Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA
    J Comp Neurol 520:2774-84. 2012
  4. pmc Neurofascin as a target for autoantibodies in peripheral neuropathies
    Judy King Man Ng
    Institute of Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany
    Neurology 79:2241-8. 2012
  5. pmc Three mechanisms assemble central nervous system nodes of Ranvier
    Keiichiro Susuki
    Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
    Neuron 78:469-82. 2013
  6. pmc Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy
    Neev Golan
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
    J Neurosci 33:10950-61. 2013
  7. pmc The making of a node: a co-production of neurons and glia
    Yael Eshed-Eisenbach
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
    Curr Opin Neurobiol 23:1049-56. 2013
  8. pmc Axonal spectrins: all-purpose fences
    Yael Eshed-Eisenbach
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
    J Cell Biol 203:381-3. 2013
  9. pmc Neuronal Ig/Caspr recognition promotes the formation of axoaxonic synapses in mouse spinal cord
    Soha Ashrafi
    Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA
    Neuron 81:120-9. 2014
  10. pmc Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits
    Olga Penagarikano
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Cell 147:235-46. 2011

Research Grants

Detail Information

Publications23

  1. pmc Essential function of protein 4.1G in targeting of membrane protein palmitoylated 6 into Schmidt-Lanterman incisures in myelinated nerves
    Nobuo Terada
    Department of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo City, Yamanashi, Japan
    Mol Cell Biol 32:199-205. 2012
    ..1G. These results indicate that 4.1G has a specific role in the targeting of MPP6 to the SLI and the assembly of these subcellular structures...
  2. pmc The cytoskeletal adapter protein 4.1G organizes the internodes in peripheral myelinated nerves
    Aleksandra Ivanovic
    Department of Molecular Neurobiology and 2 Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D 37075 Gottingen, Germany
    J Cell Biol 196:337-44. 2012
    ..These findings suggest that protein 4.1G contributes to the organization of the internodal axolemma by targeting and/or maintaining glial transmembrane proteins along the axoglial interface...
  3. ncbi Dependence of paranodal junctional gap width on transverse bands
    Jack Rosenbluth
    Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA
    J Comp Neurol 520:2774-84. 2012
    ..Surprisingly, even in the absence of TBs, paranodes are to some extent maintained in their usual form, implying that in addition to TBs, other factors govern the formation and maintenance of overall paranodal structure...
  4. pmc Neurofascin as a target for autoantibodies in peripheral neuropathies
    Judy King Man Ng
    Institute of Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany
    Neurology 79:2241-8. 2012
    ....
  5. pmc Three mechanisms assemble central nervous system nodes of Ranvier
    Keiichiro Susuki
    Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
    Neuron 78:469-82. 2013
    ..Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na⁺ channel clustering...
  6. pmc Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy
    Neev Golan
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
    J Neurosci 33:10950-61. 2013
    ..These findings indicate that Cadm4 regulates the growth of the myelin unit and the organization of the underlying axonal membrane. ..
  7. pmc The making of a node: a co-production of neurons and glia
    Yael Eshed-Eisenbach
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
    Curr Opin Neurobiol 23:1049-56. 2013
    ..In contrast, the formation of CNS nodes, which are not contacted by the myelinating glia, is surprisingly similar to the assembly of the axon initial segment and depends largely on axonal diffusion barriers. ..
  8. pmc Axonal spectrins: all-purpose fences
    Yael Eshed-Eisenbach
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
    J Cell Biol 203:381-3. 2013
    ..e., at the axonal initial segment), or by axoglial contacts (i.e., at the paranodal junction). ..
  9. pmc Neuronal Ig/Caspr recognition promotes the formation of axoaxonic synapses in mouse spinal cord
    Soha Ashrafi
    Neuroscience Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA
    Neuron 81:120-9. 2014
    ..Our findings define a recognition complex that contributes to the assembly and organization of a specialized GABAergic microcircuit. ..
  10. pmc Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits
    Olga Penagarikano
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Cell 147:235-46. 2011
    ..These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD...
  11. pmc Paranodal permeability in "myelin mutants"
    Seema Shroff
    Department Physiology and Neuroscience, NYU School of Medicine, New York, New York, USA
    Glia 59:1447-57. 2011
    ....
  12. pmc Schwann cell spectrins modulate peripheral nerve myelination
    Keiichiro Susuki
    Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 108:8009-14. 2011
    ..Therefore, we propose αII and βII spectrin in Schwann cells integrate the neuron-glia interactions mediated by membrane proteins into the actin-dependent cytoskeletal rearrangements necessary for myelination...
  13. pmc Secreted gliomedin is a perinodal matrix component of peripheral nerves
    Yael Eshed
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
    J Cell Biol 177:551-62. 2007
    ..Our results indicate that the deposition of gliomedin multimers at the nodal gap by binding to HSPGs facilitates the clustering of the axonodal CAMs and Na(+) channels...
  14. pmc A central role for Necl4 (SynCAM4) in Schwann cell-axon interaction and myelination
    Ivo Spiegel
    Department of Molecular Cell Biology, The Weizmann Institute of Science, POB 26, Rehovot 76100, Israel
    Nat Neurosci 10:861-9. 2007
    ..These results suggest that Necl proteins are important for mediating axon-glia contact during myelination in peripheral nerves...
  15. pmc Identification of Tmem10/Opalin as an oligodendrocyte enriched gene using expression profiling combined with genetic cell ablation
    Neev Golan
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
    Glia 56:1176-86. 2008
    ..These results suggest a possible role of Tmem10 in oligodendrocyte differentiation and CNS myelination...
  16. ncbi Molecular domains of myelinated axons in the peripheral nervous system
    James L Salzer
    Department of Cell Biology and Neurology, and the Smilow Neuroscience Program, NYU School of Medicine, New York, New York 10016, USA
    Glia 56:1532-40. 2008
    ..This domain organization is essential for action potential propagation by saltatory conduction and for the overall function and integrity of the axon...
  17. pmc A novel method for isolating Schwann cells using the extracellular domain of Necl1
    Ivo Spiegel
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
    J Neurosci Res 87:3288-96. 2009
    ....
  18. pmc Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B
    Ido Horresh
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
    J Neurosci 30:2480-9. 2010
    ..In accordance, we show that Caspr2 and Kv1 channels are not clustered at the JXP in 4.1B-null mice. Our results thus underscore the functional importance of protein 4.1B in the organization of peripheral myelinated axons...
  19. pmc A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier
    Konstantin Feinberg
    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
    Neuron 65:490-502. 2010
    ..Together, these two cooperating mechanisms ensure fast and efficient conduction in myelinated nerves...
  20. pmc N-WASP is required for membrane wrapping and myelination by Schwann cells
    Nurit Novak
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
    J Cell Biol 192:243-50. 2011
    ..These data suggest that regulation of actin filament nucleation in Schwann cells by N-WASP is crucial for membrane wrapping, longitudinal extension, and myelination...
  21. pmc Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia
    Eric Lancaster
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA
    Ann Neurol 69:303-11. 2011
    ....
  22. pmc Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM
    Veronique Amor
    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel W M Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, New Jersey 08854 and Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016
    J Neurosci 34:5089-98. 2014
    ....

Research Grants30

  1. Molecular Characterization of Axon-Glial Interactions
    Manzoor A Bhat; Fiscal Year: 2013
    ..abstract_text> ..