Localization of Caspr2 in Myelinated Nerves Depends on Axon–Glia Interactions and the Generation of Barriers along the Axon

Abstract

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

Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS

“…The prominent paranodal components contactin, NF-155, Caspr, and sulfatide [interacts with versican in vitro (Miura et al, 1999)] seem also not necessary for the selective deposition and binding of versican V2 at the nodes. In CGT-null mice, they are all virtually absent from the severely disturbed terminal glial loops of the paranodes (Poliak et al, 2001;Marcus et al, 2002). Nevertheless, versican V2 and TnR accumulate normally in CGT mutants, as demonstrated by our immunohistochemical analyses.…”

Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells

“…Juxtaparanodal Kv channels are composed of various heteromultimeric combinations of pore-forming Kv1 ␣ (Kv 1.1, 1.2, 1.4, and 1.6) and the associated cytoplasmic Kv␤2 subunits (42,44,47,48). In the juxtaparanodal region, Kv1.1 and Kv1.2 have been shown to colocalize with, and to interact and͞or cluster with, Caspr2, a member of the neurexin superfamily (49,50). Indeed Caspr2 also interacts with other proteins necessary for the accumulation of Kv channels at the juxtaparanodal region and for their interaction with the actin-spectrin cytoskeleton (14, [51][52][53][54][55][56].…”

Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

“…We then examined the distribution of Caspr2, a protein normally enriched in juxtaparanodes (Poliak et al, 2001), which are differentiated regions of internodes flanking the paranodes. Caspr2 distribution was altered, and its intensity appeared diminished in both P0 -SCH-⌬39 -121 and P0 -SCH-⌬Cter mice compared with wild-type mice ( Fig.…”