The Actin/Spectrin Membrane-Associated Periodic Skeleton in Neurons

Abstract

Neurons are the most asymmetric cell types, with their axons commonly extending over lengths that are thousand times longer than the diameter of the cell soma. Fluorescence nanoscopy has recently unveiled that actin, spectrin and accompanying proteins form a membrane-associated periodic skeleton (MPS) that is ubiquitously present in mature axons from all neuronal types evaluated so far. The MPS is a regular supramolecular protein structure consisting of actin "rings" separated by spectrin tetramer "spacers". Although the MPS is best organized in axons, it is also present in dendrites, dendritic spine necks and thin cellular extensions of non-neuronal cells such as oligodendrocytes and microglia. The unique organization of the actin/spectrin skeleton has raised the hypothesis that it might serve to support the extreme physical and structural conditions that axons must resist during the lifespan of an organism. Another plausible function of the MPS consists of membrane compartmentalization and subsequent organization of protein domains. This review focuses on what we know so far about the structure of the MPS in different neuronal subdomains, its dynamics and the emerging evidence of its impact in axonal biology.

Keywords: actin; axon; cytoskeleton; dendrites; fluorescence nanoscopy; spectrin; super resolution microscopy.

Figure 1

Overview of the actin/spectrin skeleton of erythrocytes. (A) Basic arrangement of the actin/spectrin skeleton underlying the erythrocyte membrane. (B) Schematic representation of the principal components of the erythrocyte membrane-cortical cytoskeleton (EMCC) and its attachments to the plasma membrane by means of the protein 4.1 and ankyrin complexes. For further details on this structure please refer to other reviews (Baines, ; Lux, 2016).

Figure 2

Overview of the membrane-associated periodic skeleton (MPS) of neurons and its associated proteins. (A) The MPS abundance and organization in different domains of a neuron, from being robust and well organized in the axon initial segment to being completely absent in the cell soma. (B) Axon shafts from sensory neurons in culture, stained against βII-spectrin and imaged by Stimulated Emission Depletion microscopy (STED) (Unsain et al., 2018), reveals the MPS. Scale bar 1 μm. (C) List of proteins arranged with a ~190 nm periodicity in axons, indicating their location with respect to the alternating actin and spectrin “stripes.” Note that the same protein can have one end in one stripe, and the other in the other stripe, as in the case of spectrins. Also, some proteins can have one of its ends interacting with the MPS and thus being periodically arranged, but have the other end freely extending out of the MPS, and thus showing no periodicity. Such is the case of ankyrin G, which has its N-terminus periodically distributed, but not its C-terminus. The components on the bottom of the list under yellow shading are exclusively found at the AIS and/or at Ranvier nodes.