Both Laminin and Schwann Cell Dystroglycan Are Necessary for Proper Clustering of Sodium Channels at Nodes of Ranvier

Abstract

Nodes of Ranvier are specialized axonal domains, at which voltage-gated sodium channels cluster. How axons cluster molecules in discrete domains is mostly unknown. Both axons and glia probably provide constraining mechanisms that contribute to domain formation. Proper sodium channel clustering in peripheral nerves depends on contact from Schwann cell microvilli, where at least one molecule, gliomedin, binds the sodium channel complex and induces its clustering. Furthermore, mice lacking Schwann cell dystroglycan have aberrant microvilli and poorly clustered sodium channels. Dystroglycan could interact at the basal lamina or at the axon-glial surface. Because dystroglycan is a laminin receptor, and laminin 2 mutations [merosin-deficient congenital muscular dystrophy (MDC1A)] cause reduced nerve conduction velocity, we asked whether laminins are involved. Here, we show that the composition of both laminins and the dystroglycan complex at nodes differs from that of internodes. Mice defective in laminin 2 have poorly formed microvilli and abnormal sodium clusters. These abnormalities are similar, albeit less severe, than those of mice lacking dystroglycan. However, mice lacking all Schwann cell laminins show severe nodal abnormalities, suggesting that other laminins compensate for the lack of laminin 2. Thus, although laminins are located at a distance from the axoglial junction, they are required for proper clustering of sodium channels. Laminins, through their specific nodal receptors and cytoskeletal linkages, may participate in the formation of mechanisms that constrain clusters at nodes. Finally, abnormal sodium channel clusters are present in a patient with MDC1A, providing a molecular basis for the reduced nerve conduction velocity in this disorder.

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

“…In addition, we detected less phospho-ERM in the microvilli and substantially more diffuse K v 1.2 staining at the juxtaparanodes in Sh3tc2 ⌬Ex1/⌬Ex1 mice. Such widening of the nodes associated with decreased phospho-ERM has been described in Laminin 2-deficient mice, where it is associated with impaired clustering of the sodium channels (23). Our data do not allow us to distinguish whether Sh3tc2 is directly involved in the formation and/or maintenance of the node of Ranvier or whether the observed nodal widening is a secondary effect of hypomyelination.…”

6 4 Integrin and Dystroglycan Cooperate to Stabilize the Myelin Sheath

“…Immunoteasing was conducted as described (Occhi et al, 2005), except for S100/β1 integrin staining where acetone was omitted, fibers were permeabilized in 0.2% triton X-100 and stained immediately after dissection.…”

“…Mice lacking Schwann cell dystroglycan present abnormalities of the nodes of Ranvier and late-onset myelin foldings (Saito et al, 2003;Occhi et al, 2005). To evaluate redundancy between the two receptors, we generated β4 integrin/DG double conditional null mice.…”

“…Dystroglycan mutants showed defective clusterization of sodium channels at nodes of Ranvier (Saito et al, 2003;Occhi et al, 2005), which was not aggravated by the lack of β4 integrin (suppl. fig.…”

“…β4 integrin cooperates with dystroglycan to mantain stability of the myelin sheath α6β4 integrin and dystroglycan are both expressed at the onset of myelination and link the cytoskeleton to laminins in the basal lamina. Dystroglycan null nerves present a late-onset instability of the myelin sheath with formation of myelin in/out-foldings resulting in motor impairment in older animals (Saito et al, 2003;Occhi et al, 2005). This neuropathy was more pronounced in the absence of both β4 integrin and dystroglycan, particularly in ventral roots of twelve month old mice where extensive myelin folding, hypomyelination and frequent signs of acute de-myelination, were observed.…”