There is much more to the nodes of Ranvier than simply being axonal segments devoid of myelin. The architecture of the region of contact between oligodendrocytes or Schwann cells and the nerve fibre is exquisitely complex, and two recent papers provide new insight on the molecular interactions between the two cell types.

The myelin sheath has been divided in several regions — paranode, juxtaparanode and internode — that have different structural and molecular signatures. The studies of Poliak et al. and Traka et al. focus on the juxtaparanode, asking what molecular interactions are necessary for its proper assembly. Previous studies had shown that K+ channels are enriched at the axonal membrane of the juxtaparanode, where they seem to interact indirectly with the protein Caspr2. The new studies provide evidence that the adhesion molecule Tag1, which is expressed by axon and glia at the juxtaparanode, is crucial for the localization of K+ channels and Caspr2.

Poliak et al. generated mice lacking Caspr2 and found that K+ channels and Tag1 were no longer abundant in the juxtaparanodes of the peripheral and central nervous systems. To study these interactions in more detail, they generated mice lacking Tag1 and found a similar phenotype: K+ channels and Caspr2 were missing from the juxtaparanode. A series of biochemical experiments helped them to obtain evidence for the direct interaction between Tag1 and Caspr2, and to show that they only interact when they form part of the same membrane and not between cells. Traka et al. did not generate Caspr2-null mice, but working with a Tag1 knockout, they obtained similar findings: the abnormal localization of K+ channels and Caspr2 in the mutant, and the interaction between Tag1 and Caspr2 in cis, but not in trans.

Both studies converge on the idea that Tag1 is crucial for the assembly of the juxtaparanode on two different fronts. First, owing to its association with Caspr2, Tag1 helps to define the molecular composition of the juxtaparanode. Second, as this adhesion molecule forms homophilic interactions between opposing membranes (in this case, between axon and glia), Tag1 participates in maintaining the structural integrity of this region of the myelin sheath.