Source: https://www.nature.com/articles/nn.3858?error=cookies_not_supported&code=f2d3f163-57d2-46e6-95fc-b9d2144620ea
Timestamp: 2019-04-20 03:28:52+00:00

Document:
Neuron-glia interactions establish functional membrane domains along myelinated axons. These include nodes of Ranvier, paranodal axoglial junctions and juxtaparanodes. Paranodal junctions are the largest vertebrate junctional adhesion complex, and they are essential for rapid saltatory conduction and contribute to assembly and maintenance of nodes. However, the molecular mechanisms underlying paranodal junction assembly are poorly understood. Ankyrins are cytoskeletal scaffolds traditionally associated with Na+ channel clustering in neurons and are important for membrane domain establishment and maintenance in many cell types. Here we show that ankyrin-B, expressed by Schwann cells, and ankyrin-G, expressed by oligodendrocytes, are highly enriched at the glial side of paranodal junctions where they interact with the essential glial junctional component neurofascin 155. Conditional knockout of ankyrins in oligodendrocytes disrupts paranodal junction assembly and delays nerve conduction during early development in mice. Thus, glial ankyrins function as major scaffolds that facilitate early and efficient paranodal junction assembly in the developing CNS.
Poliak, S. & Peles, E. The local differentiation of myelinated axons at nodes of Ranvier . Nat. Rev. Neurosci. 4, 968–980 (2003).
Babbs, C.F. & Shi, R. Subtle paranodal injury slows impulse conduction in a mathematical model of myelinated axons . PLoS ONE 8, e67767 (2013).
Chang, K.J. & Rasband, M.N. Excitable domains of myelinated nerves: axon initial segments and nodes of Ranvier . Curr. Top. Membr. 72, 159–192 (2013).
Bennett, V. & Lorenzo, D.N. Spectrin- and ankyrin-based membrane domains and the evolution of vertebrates . Curr. Top. Membr. 72, 1–37 (2013).
Bennett, V. & Healy, J. Membrane domains based on ankyrin and spectrin associated with cell-cell interactions . Cold Spring Harb. Perspect. Biol. 1, a003012 (2009).
Rasband, M.N. The axon initial segment and the maintenance of neuronal polarity . Nat. Rev. Neurosci. 11, 552–562 (2010).
Gasser, A. et al. An ankyrinG-binding motif is necessary and sufficient for targeting Nav1.6 sodium channels to axon initial segments and nodes of Ranvier . J. Neurosci. 32, 7232–7243 (2012).
Scotland, P., Zhou, D., Benveniste, H. & Bennett, V. Nervous system defects of AnkyrinB−/− mice suggest functional overlap between the cell adhesion molecule L1 and 440-kD AnkyrinB in premyelinated axons . J. Cell Biol. 143, 1305–1315 (1998).
Horresh, I., Bar, V., Kissil, J.L. & Peles, E. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B . J. Neurosci. 30, 2480–2489 (2010).
Cifuentes-Diaz, C. et al. Protein 4.1B contributes to the organization of peripheral myelinated axons . PLoS ONE 6, e25043 (2011).
Zhang, C., Susuki, K., Zollinger, D.R., Dupree, J.L. & Rasband, M.N. Membrane domain organization of myelinated axons requires βII spectrin . J. Cell Biol. 203, 437–443 (2013).
Rios, J.C. et al. Paranodal interactions regulate expression of sodium channel subtypes and provide a diffusion barrier for the node of Ranvier . J. Neurosci. 23, 7001–7011 (2003).
Hoshi, T. et al. Nodal protrusions, increased Schmidt-Lanterman incisures, and paranodal disorganization are characteristic features of sulfatide-deficient peripheral nerves . Glia 55, 584–594 (2007).
Garver, T.D., Ren, Q., Tuvia, S. & Bennett, V. Tyrosine phosphorylation at a site highly conserved in the L1 family of cell adhesion molecules abolishes ankyrin binding and increases lateral mobility of neurofascin . J. Cell Biol. 137, 703–714 (1997).
Tuvia, S., Garver, T.D. & Bennett, V. The phosphorylation state of the FIGQY tyrosine of neurofascin determines ankyrin-binding activity and patterns of cell segregation . Proc. Natl. Acad. Sci. USA 94, 12957–12962 (1997).
Jenkins, S.M. et al. FIGQY phosphorylation defines discrete populations of L1 cell adhesion molecules at sites of cell-cell contact and in migrating neurons . J. Cell Sci. 114, 3823–3835 (2001).
Bhat, M.A. et al. Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/paranodin . Neuron 30, 369–383 (2001).
Gollan, L., Salomon, D., Salzer, J.L. & Peles, E. Caspr regulates the processing of contactin and inhibits its binding to neurofascin . J. Cell Biol. 163, 1213–1218 (2003).
Kunimoto, M. A neuron-specific isoform of brain ankyrin, 440-kD ankyrinB, is targeted to the axons of rat cerebellar neurons . J. Cell Biol. 131, 1821–1829 (1995).
Cunha, S.R., Le Scouarnec, S., Schott, J.J. & Mohler, P.J. Exon organization and novel alternative splicing of the human ANK2 gene: implications for cardiac function and human cardiac disease . J. Mol. Cell. Cardiol. 45, 724–734 (2008).
Rueckert, E.H. et al. Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder . Mol. Psychiatry 18, 922–929 (2013).
Davis, J.Q., Lambert, S. & Bennett, V. Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments . J. Cell Biol. 135, 1355–1367 (1996).
Tait, S. et al. An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction . J. Cell Biol. 150, 657–666 (2000).
Susuki, K. & Rasband, M.N. Spectrin and ankyrin-based cytoskeletons at polarized domains in myelinated axons . Exp. Biol. Med. (Maywood) 233, 394–400 (2008).
Susuki, K. et al. Schwann cell spectrins modulate peripheral nerve myelination . Proc. Natl. Acad. Sci. USA 108, 8009–8014 (2011).
Hammarlund, M., Jorgensen, E.M. & Bastiani, M.J. Axons break in animals lacking β-spectrin . J. Cell Biol. 176, 269–275 (2007).
Eisenbach, M. et al. Differential clustering of Caspr by oligodendrocytes and Schwann cells . J. Neurosci. Res. 87, 3492–3501 (2009).
Einheber, S. et al. The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons . Glia 61, 240–253 (2013).
Zhang, X., Davis, J.Q., Carpenter, S. & Bennett, V. Structural requirements for association of neurofascin with ankyrin . J. Biol. Chem. 273, 30785–30794 (1998).
Ren, Q. & Bennett, V. Palmitoylation of neurofascin at a site in the membrane-spanning domain highly conserved among the L1 family of cell adhesion molecules . J. Neurochem. 70, 1839–1849 (1998).
Shi, L. et al. Whole-genome sequencing in an autism multiplex family . Mol. Autism 4, 8 (2013).
Iqbal, Z. et al. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders . Hum. Mol. Genet. 22, 1960–1970 (2013).
Yuan, A. et al. ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis . Am. J. Med. Genet. B. Neuropsychiatr. Genet. 159B, 997–1005 (2012).
Leussis, M.P., Madison, J.M. & Petryshen, T.L. Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology . Biol. Mood Anxiety Disord. 2, 18 (2012).
Rhodes, K.J., Keilbaugh, S.A., Barrezueta, N.X., Lopez, K.L. & Trimmer, J.S. Association and colocalization of K+ channel α- and β-subunit polypeptides in rat brain . J. Neurosci. 15, 5360–5371 (1995).
Schafer, D.P., Custer, A.W., Shrager, P. & Rasband, M.N. Early events in node of Ranvier formation during myelination and remyelination in the PNS . Neuron Glia Biol. 2, 69–79 (2006).
Ivanovic, A. et al. The cytoskeletal adapter protein 4.1G organizes the internodes in peripheral myelinated nerves . J. Cell Biol. 196, 337–344 (2012).
Chang, K.J., Susuki, K., Dours-Zimmermann, M.T., Zimmermann, D.R. & Rasband, M.N. Oligodendrocyte myelin glycoprotein does not influence node of Ranvier structure or assembly . J. Neurosci. 30, 14476–14481 (2010).
E. Peles (Weizmann Institute of Science) provided NfascF/F mice and 4.1G antibodies. K.-A. Nave (Max Planck Institute of Experimental Medicine) provided Cnp-Cre mice. P.M. Jenkins (Duke University) provided AnkG 480/270 antibodies. This work was supported by grants from the US National Institutes of Health (NS069688 and NS044916 to M.N.R.; HL084583, HL083422 and HL114383 to P.J.M.), the National Multiple Sclerosis Society (M.N.R.) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (M.N.R.). V.B. is an investigator of the Howard Hughes Medical Institute.
Present address: Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
Departments of Physiology and Cell Biology, Internal Medicine, and the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
M.N.R. and K.-J.C. conceived the project, designed the experiments and wrote the manuscript. D.R.Z. and K.S. did electrophysiology experiments and analyzed the data. D.R.Z. conducted the electron microscopy experiments. K.-J.C. did all other experiments and analyzed the data. P.J.M. and M.A.M. designed and constructed the Ank2F/F allele. D.L.S., P.J.B., E.C.C. and V.B. provided reagents and mice.
Paranodal junction assembly is disrupted in the CNS of AnkB/G-cKO mice.
The summary and implications of this study.
The full immunoblots of Figs. 1e, 6e and 6f.
The full immunoblots of Figs. 3i, 7b, 7c and 8b.

References: V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V. 
 V.