Axon-Glia Interactions and the Domain Organization of Myelinated Axons Requires Neurexin IV/Caspr/Paranodin

Abstract

Myelinated fibers are organized into distinct domains that are necessary for saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where glial cells closely appose and form specialized septate-like junctions with axons. These junctions contain a Drosophila Neurexin IV-related protein, Caspr/Paranodin (NCP1). Mice that lack NCP1 exhibit tremor, ataxia, and significant motor paresis. In the absence of NCP1, normal paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Contactin is undetectable in the paranodes, and K(+) channels are displaced from the juxtaparanodal into the paranodal domains. Loss of NCP1 also results in a severe decrease in peripheral nerve conduction velocity. These results show a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions required for normal saltatory conduction.

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

“…12 Caspr interacts with Contactin-1, which is a glycosyl phosphatidyl inositolanchored neural cell adhesion molecule, to form an extracellular complex with neurofascin resulting to axoglial junction. 8,13 The missense variant identified in our family is located in a disulfide bond within a laminin G domain, in the extracellular region of Caspr, which seems to be involved in molecular interaction between Caspr and Contactin-1. This variant likely interferes with adhesion process at axoglial junction and explains the abnormal myelin organization.…”

“…14 Mice lacking Caspr displayed growth failure with severe neurological defects, including cerebellar syndrome, generalized motor paresis and premature death. 8 Absence of Caspr resulted in altered distribution of juxtaparanodal components, including Kv1 channels and contactin-1. 15 Finally, dissociations of the myelin loops from the axons were described in optic nerves of Cntn1-KO mice.…”

“…7 CNTNAP1 encodes Caspr that is essential to the paranodal junctions. 8 We report on two brothers affected with hypotonia and CHN caused by compound heterozygous CNTNAP1 variants.…”

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

“…In the zebrafish embryo, erbb3 has been shown to be specifically required for migration and proliferation of Schwann cell precursors (Lyons et al, 2005). CNTNAP1 on the other hand, mediates axon-glial contacts in paranodal regions and its loss affects saltatory nerve conduction (Bhat et al, 2001). …”

Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves

“…Contactin, residing in the axonal membrane, brings the other proteins to the handshake. Deficiency in either caspr, contactin, or neurofascin 155 produces a disorganization of the paranodal loops and a reduction in axon conduction velocity (Bhat et al, 2001;Bonnon et al, 2007;Boyle et al, 2001;Sherman et al, 2005). At the nodal/paranodal region in the myelinated axons of sciatic nerves of mice deficient in caspr, PJBs were missing and abnormal, swollen mitochondria were observed (Einheber et al, 2006).…”