Structure and function of subcortical periodic cytoskeleton throughout the nervous system

  • Cenfeng Chu iHuman Institute, ShanghaiTech University, Shanghai, China
  • Guisheng Zhong iHuman Institute, ShanghaiTech University, Shanghai, China
  • Hui Li iHuman Institute, ShanghaiTech University, Shanghai, China
Keywords: Cytoskeleton, Super-resolution microscopy, Nervous system, Spectrin, Actin


Cytoskeleton plays an essential role in many functions in different cells and has been involved in the pathogenesis of many neural diseases. With the development of super-resolution fluorescence imaging technologies, which combine the molecular specificity and simple sample preparation of fluorescence microscopy and provide a spatial resolution comparable to that of electron microscopy, numerous new features have been revealed in the cytoskeletal organization of the subcortical cytoskeleton. A novel periodic lattice cytoskeleton is prevalent in different cell types throughout the nervous system. Here, we review the current studies of the molecular distribution, developmental mechanisms, and functional properties of the periodic cytoskeleton structure.


Kevenaar JT, Hoogenraad CC. The axonal cytoskeleton: from organization to function. Front Mol Neurosci. 2015;8:44.

Zhong G, He J, Zhou R, Lorenzo D, Babcock HP, Bennett V, et al. Developmental mechanism of the periodic membrane

skeleton in axons. Elife. 2014;3.

Xu K, Zhong G, Zhuang X. Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons.

Science. 2013;339(6118):452-6.

Lukinavicius G, Reymond L, D'Este E, Masharina A, Gottfert F, Ta H, et al. Fluorogenic probes for live-cell imaging of the cytoskeleton. Nat Methods. 2014;11(7):731-3.

D'Este E, Kamin D, Gottfert F, El-Hady A, Hell SW. STED nanoscopy reveals the ubiquity of subcortical cytoskeleton

periodicity in living neurons. Cell Rep. 2015;10(8):1246-51.

D'Este E, Kamin D, Velte C, Gottfert F, Simons M, Hell SW. Subcortical cytoskeleton periodicity throughout the nervous

system. Sci Rep. 2016;6:22741.

He J, Zhou R, Wu Z, Carrasco MA, Kurshan PT, Farley JE, et al. Prevalent presence of periodic actin-spectrinbased

membrane skeleton in a broad range of neuronal cell types and animal species. Proc Natl Acad Sci USA. 2016;113(21):6029-34.

Sidenstein SC, D'Este E, Bohm MJ, Danzl JG, Belov VN, Hell SW. Multicolour multilevel STED nanoscopy of actin/

spectrin organization at synapses. Sci Rep. 2016;6:26725.

Byers TJ, Branton D. Visualization of the protein associations in the erythrocyte membrane skeleton. Proc

Natl Acad Sci USA. 1985;82(18):6153-7.

Liu SC, Derick LH, Palek J. Visualization of the hexagonal lattice in the erythrocyte membrane skeleton. J Cell Biol.


Bennett V, Lorenzo DN. Spectrin- and ankyrin-based membrane domains and the evolution of vertebrates. Curr Top Membr. 2013;72:1-37.

Bennett V, Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol Rev. 2001;81(3):1353-92.

An X, Lecomte MC, Chasis JA, Mohandas N, Gratzer W. Shear-response of the spectrin dimer-tetramer equilibrium in the red blood cell membrane. J Biol Chem. 2002;277(35):31796-800.

Fowler VM. The human erythrocyte plasma membrane: a Rosetta Stone for decoding membrane-cytoskeleton

structure. Curr Top Membr. 2013;72:39-88.

Fischer RS, Fowler VM. Tropomodulins: life at the slow end. Trends Cell Biol. 2003;13(11):593-601.

An X, Salomao M, Guo X, Gratzer W, Mohandas N. Tropomyosin modulates erythrocyte membrane stability.

Blood. 2007;109(3):1284-8.

Korobova F, Svitkina T. Molecular architecture of synaptic actin cytoskeleton in hippocampal neurons reveals a

mechanism of dendritic spine morphogenesis. Mol Biol Cell. 2010;21(1):165-76.

Jones SL, Korobova F, Svitkina T. Axon initial segment cytoskeleton comprises a multiprotein submembranous

coat containing sparse actin filaments. J Cell Biol. 2014;205(1):67-81.

Pielage J, Cheng L, Fetter RD, Carlton PM, Sedat JW, Davis GW. A presynaptic giant ankyrin stabilizes the NMJ through regulation of presynaptic microtubules and transsynaptic cell adhesion. Neuron. 2008;58(2):195-209.

Leite SC, Sampaio P, Sousa VF, Nogueira-Rodrigues J, Pinto-Costa R, Peters LL, et al. The Actin-Binding Protein

alpha-Adducin Is Required for Maintaining Axon Diameter. Cell Rep. 2016;15(3):490-8.

Bradke F, Dotti CG. The role of local actin instability in axon formation. Science. 1999;283(5409):1931-4.

Riederer BM, Zagon IS, Goodman SR. Brain spectrin(240/235) and brain spectrin(240/235E): two distinct spectrin subtypes with different locations within mammalian neural cells. J Cell Biol. 1986;102(6):2088-97.

Galiano MR, Jha S, Ho TS, Zhang C, Ogawa Y, Chang KJ, et al. A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell. 2012;149(5):1125-39.

Lorenzo DN, Badea A, Davis J, Hostettler J, He J, Zhong G, et al. A PIK3C3-ankyrin-B-dynactin pathway promotes axonal growth and multiorganelle transport. J Cell Biol. 2014;207(6):735-52.

McGough A, Pope B, Chiu W, Weeds A. Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function. J Cell Biol. 1997;138(4):771-81.

Munsie LN, Caron N, Desmond CR, Truant R. Lifeact cannot visualize some forms of stress-induced twisted F-actin. Nat Methods. 2009;6(5):317.

Sakaguchi G, Orita S, Naito A, Maeda M, Igarashi H, Sasaki T, et al. A novel brain-specific isoform of beta spectrin: isolation and its interaction with Munc13. Biochem Biophys Res Commun. 1998;248(3):846-51.

Stankewich MC, Tse WT, Peters LL, Ch'ng Y, John KM, Stabach PR, et al. A widely expressed betaIII spectrin associated with Golgi and cytoplasmic vesicles. Proc Natl Acad Sci USA. 1998;95(24):14158-63.

Gao Y, Perkins EM, Clarkson YL, Tobia S, Lyndon AR, Jackson M, et al. beta-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis. J Neurosci. 2011;31(46):16581-90.

Paramore S, Ayton GS, Mirijanian DT, Voth GA. Extending a spectrin repeat unit. I: linear force-extension response. Biophys J. 2006;90(1):92-100.

Hammarlund M, Jorgensen EM, Bastiani MJ. Axons break in animals lacking beta-spectrin. J Cell Biol. 2007;176(3):269-75.

Krieg M, Dunn AR, Goodman MB. Mechanical control of the sense of touch by beta-spectrin. Nat Cell Biol. 2014;16(3):224-33.

Leterrier C, Potier J, Caillol G, Debarnot C, Rueda Boroni F, Dargent B. Nanoscale architecture of the axon initial segment reveals an organized and robust scaffold. Cell Rep. 2015;13(12):2781-93.

Tseng WC, Jenkins PM, Tanaka M, Mooney R, Bennett V. Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors. Proc Natl Acad Sci USA. 2015;112(4):1214-9.

Jenkins PM, He M, Bennett V. Dynamic spectrin/ankyrin-G microdomains promote lateral membrane assembly by opposing endocytosis. Sci Adv. 2015;1(8):e1500301.

Grubb MS, Shu Y, Kuba H, Rasband MN, Wimmer VC, Bender KJ. Short- and long-term plasticity at the axon initial segment. J Neurosci. 2011;31(45):16049-55.

Zhang C, Rasband MN. Cytoskeletal control of axon domain assembly and function. Curr Opin Neurobiol. 2016;39:116-21.

Kole MH, Ilschner SU, Kampa BM, Williams SR, Ruben PC, Stuart GJ. Action potential generation requires a high sodium channel density in the axon initial segment. Nat Neurosci. 2008;11(2):178-86.

Sherman DL, Tait S, Melrose S, Johnson R, Zonta B, Court FA, et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron. 2005;48(5):737-42.

Susuki K, Rasband MN. Spectrin and ankyrin-based cytoskeletons at polarized domains in myelinated axons. Exp Biol Med (Maywood). 2008;233(4):394-400.

Dzhashiashvili Y, Zhang Y, Galinska J, Lam I, Grumet M, Salzer JL. Nodes of Ranvier and axon initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J Cell Biol. 2007;177(5):857-70.

Gasser A, Ho TS, Cheng X, Chang KJ, Waxman SG, Rasband MN, 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. 2012;32(21):7232-43.

Yang Y, Ogawa Y, Hedstrom KL, Rasband MN. betaIV spectrin is recruited to axon initial segments and nodes of Ranvier by ankyrinG. J Cell Biol. 2007;176(4):509-19.

Susuki K, Chang KJ, Zollinger DR, Liu Y, Ogawa Y, Eshed-Eisenbach Y, et al. Three mechanisms assemble central nervous system nodes of Ranvier. Neuron. 2013;78(3):469-82.

D'Este E, Kamin D, Balzarotti F, Hell SW. Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy. Proc Natl Acad Sci USA. 2016.

Ho TS, Zollinger DR, Chang KJ, Xu M, Cooper EC, Stankewich MC, et al. A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier. Nat Neurosci. 2014;17(12):1664-72.

Jones SL, Svitkina TM. Axon initial segment cytoskeleton: architecture, development, and role in neuron polarity. Neural Plast. 2016;2016:6808293.

Honigmann A, Mueller V, Ta H, Schoenle A, Sezgin E, Hell SW, et al. Scanning STED-FCS reveals spatiotemporal heterogeneity of lipid interaction in the plasma membrane of living cells. Nat Commun. 2014;5.

Bates M, Huang B, Dempsey GT, Zhuang X. Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science. 2007;317(5845):1749-53.

Goellner B, Aberle H. The synaptic cytoskeleton in development and disease. Dev Neurobiol. 2012;72(1):111-25.

Ruiz-Canada C, Budnik V. Synaptic cytoskeleton at the neuromuscular junction. Int Rev Neurobiol. 2006;75:217-36.

Susuki K, Raphael AR, Ogawa Y, Stankewich MC, Peles E, Talbot WS, et al. Schwann cell spectrins modulate peripheral nerve myelination. Proc Natl Acad Sci USA. 2011;108(19):8009-14.

Goodman SR, Lopresti LL, Riederer BM, Sikorski A, Zagon IS. Brain spectrin(240/235A): a novel astrocyte specific spectrin isoform. Brain Res Bull. 1989;23(4-5):311-6.

Zhou RB, Han BR, Xia CL, Zhuang XW. Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons. Science. 2019;365(6456):929-+.

Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161-202.

Bar J, Kobler O, van Bommel B, Mikhaylova M. Periodic F-actin structures shape the neck of dendritic spines. Sci Rep. 2016;6:37136.

How to Cite
Chu, C., Zhong, G., & Li, H. (2020). Structure and function of subcortical periodic cytoskeleton throughout the nervous system. STEMedicine, 1(1), e9.
Review articles