Nodes of Ranvier and Axon Initial Segments Are Ankyrin G-dependent Domains That Assemble by Distinct Mechanisms

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2007 Jun 6

PMID 17548513

Citations 112

Authors

Yulia Dzhashiashvili

Yanqing Zhang

Jolanta Galinska

Isabel Lam

Martin Grumet

James L Salzer

Affiliations

Soon will be listed here.

Abstract

Axon initial segments (AISs) and nodes of Ranvier are sites of action potential generation and propagation, respectively. Both domains are enriched in sodium channels complexed with adhesion molecules (neurofascin [NF] 186 and NrCAM) and cytoskeletal proteins (ankyrin G and betaIV spectrin). We show that the AIS and peripheral nervous system (PNS) nodes both require ankyrin G but assemble by distinct mechanisms. The AIS is intrinsically specified; it forms independent of NF186, which is targeted to this site via intracellular interactions that require ankyrin G. In contrast, NF186 is targeted to the node, and independently cleared from the internode, by interactions of its ectodomain with myelinating Schwann cells. NF186 is critical for and initiates PNS node assembly by recruiting ankyrin G, which is required for the localization of sodium channels and the entire nodal complex. Thus, initial segments assemble from the inside out driven by the intrinsic accumulation of ankyrin G, whereas PNS nodes assemble from the outside in, specified by Schwann cells, which direct the NF186-dependent recruitment of ankyrin G.

Citing Articles

Deletion in Purkinje Neurons Disrupts the Axon Initial Segment, Impairing Excitability and Cerebellar Function.

Brown S, Jena A, Osko J, Ransdell J bioRxiv. 2025; .

PMID: 39974887 PMC: 11838410. DOI: 10.1101/2025.01.31.635932.

Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice.

Thome C, Janssen J, Karabulut S, Acuna C, DEste E, Soyka S Elife. 2025; 12.

PMID: 39898808 PMC: 11790247. DOI: 10.7554/eLife.87078.

Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice.

Thome C, Janssen J, Karabulut S, Acuna C, DEste E, Soyka S bioRxiv. 2024; .

PMID: 38948770 PMC: 11212890. DOI: 10.1101/2023.02.01.525891.

Location of the axon initial segment assembly can be predicted from neuronal shape.

Xu Z, Angstmann C, Wu Y, Stefen H, Paric E, Fath T iScience. 2024; 27(3):109264.

PMID: 38450155 PMC: 10915628. DOI: 10.1016/j.isci.2024.109264.

Glia trigger endocytic clearance of axonal proteins to promote rodent myelination.

Bekku Y, Zotter B, You C, Piehler J, Leonard W, Salzer J Dev Cell. 2024; 59(5):627-644.e10.

PMID: 38309265 PMC: 11089820. DOI: 10.1016/j.devcel.2024.01.008.

References

Winckler B . Scientiae forum / models and speculations pathways for axonal targeting of membrane proteins. Biol Cell. 2004; 96(9):669-74. DOI: 10.1016/j.biolcel.2004.05.005. View

Hortsch M . Structural and functional evolution of the L1 family: are four adhesion molecules better than one?. Mol Cell Neurosci. 2000; 15(1):1-10. DOI: 10.1006/mcne.1999.0809. View

Dillon C, Sandy P, Nencioni A, Kissler S, Rubinson D, Van Parijs L . Rnai as an experimental and therapeutic tool to study and regulate physiological and disease processes. Annu Rev Physiol. 2005; 67:147-73. DOI: 10.1146/annurev.physiol.67.040403.130716. View

Xu X, Shrager P . Dependence of axon initial segment formation on Na+ channel expression. J Neurosci Res. 2005; 79(4):428-41. DOI: 10.1002/jnr.20378. View

Eshed Y, Feinberg K, Poliak S, Sabanay H, Sarig-Nadir O, Spiegel I . Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier. Neuron. 2005; 47(2):215-29. DOI: 10.1016/j.neuron.2005.06.026. View

Sherman D, Tait S, Melrose S, Johnson R, Zonta B, Court F . Neurofascins are required to establish axonal domains for saltatory conduction. Neuron. 2005; 48(5):737-42. DOI: 10.1016/j.neuron.2005.10.019. View

Pan Z, Kao T, Horvath Z, Lemos J, Sul J, Cranstoun S . A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci. 2006; 26(10):2599-613. PMC: 6675151. DOI: 10.1523/JNEUROSCI.4314-05.2006. View

Koticha D, Maurel P, Zanazzi G, Kane-Goldsmith N, Basak S, Babiarz J . Neurofascin interactions play a critical role in clustering sodium channels, ankyrin G and beta IV spectrin at peripheral nodes of Ranvier. Dev Biol. 2006; 293(1):1-12. DOI: 10.1016/j.ydbio.2005.05.028. View

Lai H, Jan L . The distribution and targeting of neuronal voltage-gated ion channels. Nat Rev Neurosci. 2006; 7(7):548-62. DOI: 10.1038/nrn1938. View

10.

Nagaraj K, Hortsch M . Phosphorylation of L1-type cell-adhesion molecules--ankyrins away!. Trends Biochem Sci. 2006; 31(10):544-6. DOI: 10.1016/j.tibs.2006.07.010. View

11.

Ching W, Zanazzi G, Levinson S, Salzer J . Clustering of neuronal sodium channels requires contact with myelinating Schwann cells. J Neurocytol. 2000; 28(4-5):295-301. DOI: 10.1023/a:1007053411667. View

12.

Bennett V, Lambert S . Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels. J Neurocytol. 2000; 28(4-5):303-18. DOI: 10.1023/a:1007005528505. View

13.

Malhotra J, Hortsch M, Isom L . Sodium channel beta subunits mediate homophilic cell adhesion and recruit ankyrin to points of cell-cell contact. J Biol Chem. 2001; 275(15):11383-8. DOI: 10.1074/jbc.275.15.11383. View

14.

Berghs S, Aggujaro D, Dirkx Jr R, Maksimova E, Stabach P, Hermel J . betaIV spectrin, a new spectrin localized at axon initial segments and nodes of ranvier in the central and peripheral nervous system. J Cell Biol. 2000; 151(5):985-1002. PMC: 2174349. DOI: 10.1083/jcb.151.5.985. View

15.

Rios J, Zanazzi G, Lambert S, BRETSCHER A, Salzer J . Nodes of Ranvier form in association with ezrin-radixin-moesin (ERM)-positive Schwann cell processes. Proc Natl Acad Sci U S A. 2001; 98(3):1235-40. PMC: 14738. DOI: 10.1073/pnas.98.3.1235. View

16.

Koroll M, Rathjen F, Volkmer H . The neural cell recognition molecule neurofascin interacts with syntenin-1 but not with syntenin-2, both of which reveal self-associating activity. J Biol Chem. 2001; 276(14):10646-54. DOI: 10.1074/jbc.M010647200. View

17.

Lustig M, Erskine L, Mason C, Grumet M, Sakurai T . Nr-CAM expression in the developing mouse nervous system: ventral midline structures, specific fiber tracts, and neuropilar regions. J Comp Neurol. 2001; 434(1):13-28. DOI: 10.1002/cne.1161. View

18.

Ratcliffe C, Westenbroek R, Curtis R, Catterall W . Sodium channel beta1 and beta3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain. J Cell Biol. 2001; 154(2):427-34. PMC: 2150779. DOI: 10.1083/jcb.200102086. View

19.

Jenkins S, Kizhatil K, Kramarcy N, Sen A, Sealock R, Bennett V . FIGQY phosphorylation defines discrete populations of L1 cell adhesion molecules at sites of cell-cell contact and in migrating neurons. J Cell Sci. 2001; 114(Pt 21):3823-35. DOI: 10.1242/jcs.114.21.3823. View

20.

Jenkins S, Bennett V . Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments. J Cell Biol. 2001; 155(5):739-46. PMC: 2150881. DOI: 10.1083/jcb.200109026. View