Neurofascin Is a Glial Receptor for the Paranodin/Caspr-Contactin Axonal Complex at the Axoglial Junction

Abstract

In myelinated fibers of the vertebrate nervous system, glial-ensheathing cells interact with axons at specialized adhesive junctions, the paranodal septate-like junctions. The axonal proteins paranodin/Caspr and contactin form a cis complex in the axolemma at the axoglial adhesion zone, and both are required to stabilize the junction. There has been intense speculation that an oligodendroglial isoform of the cell adhesion molecule neurofascin, NF155, expressed at the paranodal loop might be the glial receptor for the paranodin/Caspr-contactin complex, particularly since paranodin/Caspr and NF155 colocalize to ectopic sites in the CNS of the dysmyelinated mouse Shiverer mutant. We report that the extracellular domain of NF155 binds specifically to transfected cells expressing the paranodin/Caspr-contactin complex at the cell surface. This region of NF155 also binds the paranodin/Caspr-contactin complex from brain lysates in vitro. In support of the functional significance of this interaction, NF155 antibodies and the extracellular domain of NF155 inhibit myelination in myelinating cocultures, presumably by blocking the adhesive relationship between the axon and glial cell. These results demonstrate that the paranodin/Caspr-contactin complex interacts biochemically with NF155 and that this interaction is likely to be biologically relevant at the axoglial junction.

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

“…Alternatively, CASPR2 may function by transducing an extracellular signal or by enabling another growth-factor receptor to transduce such a signal. Moreover, in Drosophila the CASPR2 homolog neurexin IV binds not only to contactins similar to its vertebrate counterpart (33) but also to other Ig-domain proteins such as neurofascin, wrapper, and roundabout (40)(41)(42). In addition, contactins bind to receptor phospho-tyrosine phosphatases (43,44), which may mediate dendritic growth signaling via the protein tyrosine kinase fyn (45).…”

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

“…In contrast to NCP1 Ϫ/Ϫ , the CGT mutants express normal levels of NCP1, but the localization at the AGJs is disrupted. CGT is required for the segregation of lipid microdomains for the clustering of NF155, the glial-binding partner of the axonal paranodal complex (8,22). Most importantly, one would not expect CGT mutation to affect NCP1 function that is not related to AGJ formation because the absence of CGT is hypothesized to affect the clustering of the NF155-based glial complex, which is the binding partner for the NCP1͞CNTN-based axonal complex at AGJs.…”

“…Three major proteins have been shown to localize to the paranodal AGJs: NCP1 (also known as Caspr1 or paranodin) and contactin (CNTN) on the axonal side and neurofascin (NF155), the 155-kDa isoform on the glial side (5)(6)(7)(8)(9). Although NF155 is the only known glial protein at the paranodal membrane, a number of nonparanodal glial proteins are required for proper formation, maintenance, and distribution of AGJs, as in the case of ceramide galactosyltransferase (CGT), proteolipid protein, myelin-basic protein, myelin-associated glycoprotein, 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase, and the transcription factor Nkx6-2 (10)(11)(12)(13)(14)(15)(16)(17).…”

Rafts in oligodendrocytes: Evidence and structure–function relationship

“…NF155 is localized within the paranodal loops where it interacts with the Caspr1 (contactin-associated protein, also known as paranodin)-F3/contactin protein complex on the axon (Charles et al, 2002;Tait et al, 2000), an interaction that is required for myelination in co-cultures of OLGs and neurons (Charles et al, 2002). The finding that NF155 is completely absent from paranodes of CGT (ceramide galactosyl transferase) knockout mice (Menon et al, 2003) indicates that raft assembly might be critical for the accumulation of NF155 in paranodes.…”