| First Author | Huang CY | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 47 | Pages | 11323-11334 |
| PubMed ID | 29038243 | Mgi Jnum | J:254074 |
| Mgi Id | MGI:6101298 | Doi | 10.1523/JNEUROSCI.2113-17.2017 |
| Citation | Huang CY, et al. (2017) An alphaII Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration. J Neurosci 37(47):11323-11334 |
| abstractText | 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 alphaII 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 alphaII spectrin-deficient mice of both sexes and found that, in myelinated axons, alphaII spectrin forms a periodic cytoskeleton with betaIV and betaII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of alphaII 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 betaIV spectrin is constant among axons, but the density of nodal alphaII 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 alphaII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that alphaII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier.SIGNIFICANCE STATEMENT A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in maintenance of axon integrity. We demonstrate the role of the periodic spectrin-dependent cytoskeleton in axons and show that loss of alphaII spectrin from PNS axons causes preferential degeneration of large-diameter myelinated axons. We show that nodal alphaII spectrin is found at greater densities in large-diameter myelinated axons, suggesting that nodes are particularly vulnerable domains requiring a specialized cytoskeleton to protect against axon degeneration. |
