Localization of Caspr2 in myelinated nerves depends on axon-glia interactions and the generation of barriers along the axon

Cell recognition proteins of the contactin-associated protein (Caspr) famil y demarcate distinct domains along myelinated axons. Caspr is present at th e paranodal junction formed between the axon and myelinating glial cells, w hereas Caspr2 is localized and associates with K+ channels at the adjacent juxtaparanodal region. Here we investigated the distribution of Caspr2 duri ng development of peripheral nerves of normal and galactolipids-deficient [ ceramide galactosyl transferase (CGT)-/-] mice. This mutant exhibits parano dal abnormalities, lacking all putative adhesion components of this junctio n, including Caspr, contactin, and neurofascin 155. in sciatic nerves of th is mutant, Caspr2 was not found at the juxtaparanodal region but was concen trated instead at the paranodes with Kv1.2. Similar distribution of Gaspr2 was found in the PNS of contactin knock-out mice, which also lack Caspr in their paranodes. During development of wild-type peripheral nerves, Gaspr2 and Kv1.2 were initially detected at the paranodes before relocating to the adjacent juxtaparanodal region. This transition was not observed in CGT mi ce, where Caspr2 and Kv1.2 remained paranodal. Double labeling for Caspr an d Caspr2 demonstrated that these two related proteins occupied mutually exc luding domains along the axon and revealed the presence of both paranodal a nd internodal barrier-like structures that are delineated by Caspr. Finally , we found that the disruption of axon-glia contact in CGT-/- nerves also a ffects the localization of the cytoskeleton-associated protein 4.1 B along the axon. Altogether, our results reveal a sequential appearance of members of the Caspr family at different domains along myelinated axons and sugges t that the localization of Caspr2 may be controlled by the generation of Ca spr-containing barriers along the axon.