An αII Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration
Résumé
Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with II spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed II spectrin-deficient mice of both sexes and found that, in myelinated axons, II spectrin forms a periodic cytoskeleton with IV and II spectrin at nodes of Ranvier and paranodes, respectively, but that loss of II spectrin disrupts this organization. Avil-cre;Sptan1 f/f mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K channels. We show that the density of nodal IV spectrin is constant among axons, but the density of nodal II spectrin increases with axon diameter. Remarkably, Avil-cre;Sptan1 f/f mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal II spectrin helps resist the mechanical forces experienced by large-diameter axons, and that II spectrin-dependent cytoskel-etons are also required for assembly of nodes of Ranvier.
Domaines
Neurobiologie
Origine : Accord explicite pour ce dépôt
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