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.

Axo-glial junctions (AGJs) play a critical role in the organization and maintenance of molecular domains in myelinated axons. Neurexin IV͞Caspr1͞paranodin (NCP1) is an important player in the formation of AGJs because it recruits a paranodal complex implicated in the tethering of glial proteins to the axonal membrane and cytoskeleton. Mice deficient in either the axonal protein NCP1 or the glial ceramide galactosyltransferase (CGT) display disruptions in AGJs and severe ataxia. In this article, we correlate these two phenotypes and show that both NCP1 and CGT mutants develop large swellings accompanied by cytoskeletal disorganization and degeneration in the axons of cerebellar Purkinje neurons. We also show that ␣II spectrin is part of the paranodal complex and that, although not properly targeted, this complex is still formed in CGT mutants. Together, these findings establish a physiologically relevant link between AGJs and axonal cytoskeleton and raise the possibility that some neurodegenerative disorders arise from disruption of the AGJs.myelin ͉ paranodes ͉ cerebellum ͉ ataxia T he anatomical organization of myelinated fibers into distinct domains is the basis for the saltatory mode of action potential propagation. In the axons, these molecular domains (internode, juxtaparanode, paranode, and node of Ranvier) form as a result of specific polarization driven by signaling between the myelinating glial cells and neurons that has yet to be fully understood. In the paranodal region, closely apposed axon-glial membranes form specialized cell junctions, which resemble the ladder-like invertebrate septate junctions, and are referred to as paranodal septate junctions or paranodal axo-glial junctions (AGJs) (1-4).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 (5-9). 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 (10-17).Genetic ablation of NCP1 and CNTN in mice results in the loss of AGJs and a failure to segregate Na ϩ and K ϩ channels at the nodes and juxtaparanodes, respectively (5, 6). Similar phenotypes were observed at the paranodes in CGT mutants (18,19). CGT encodes an enzyme that is needed for the biosynthesis of two important myelin lipids, galactocerebroside and sulfatide (10,(18)(19)(20)(21). Using subcellular fractionation of NF155 in detergents, Rasband and coworkers (22) proposed a model in which myelin lipids assemble in stable lipid rafts to stabilize the clustering of NF155 at the glial side of AGJs. This model is consistent with the phenotype of CGT mutants in which defective biosynthes...

Myelinated axons are endowed with a specialized domain structure that is essential for saltatory action potential conduction. The paranodal domain contains the axoglial junctions and displays a unique ultrastructure that resembles the invertebrate septate junctions (SJs). Biochemical characterizations of the paranodal axoglial SJs have identified several molecular components that include Caspr and contactin (Cont) on the axonal side and neurofascin 155 kDa (NF155) isoform on the glial side. All these proteins are essential for the formation of the axoglial SJs. Based on the interactions between Caspr and Cont and their colocalization in the CA1 synaptic areas, it was proposed that the synaptic function of Cont requires Caspr. Here we have extended the phenotypic analysis of CASPR mutants to address further the role of Caspr at the axoglial SJs and also in axonal orientation and synaptic plasticity. We report that, in CASPR mutants, the smooth endoplasmic reticulum (SER) forms elongated membranous complexes that accumulate at the nodal/ paranodal region and stretch into the juxtaparanodal region, a defect that is consistent with the paranodal disorganization. We show that the cerebellar microorganization is unaffected in CASPR mutants. We also demonstrate that Caspr function is not essential for normal CA1 synaptic transmission and plasticity. Taken together with previous findings, our results highlight that the Caspr/ Cont complex is essential for the formation of axoglial SJs, whereas Cont may regulate axonal orientation and synaptic plasticity independent of its association with Caspr. In vertebrates, myelination provides axonal insulation and organizes axons into unique domains that are distinct in their molecular composition (Bhat, 2003a;Salzer, 2003;Schafer and Rasband, 2006). This domain organization allows myelinated axons to propagate action potentials in a saltatory manner. The molecular mechanisms that underlie the organization of these domains are still poorly understood. Over the past decade, many molecules have been identified that specifically localize to nodes of Ranvier, the paranodes, and the juxtaparanodes (Poliak and Peles, 2003). The paranodal region of the myelinated axons displays specialized structural attributes with ladder-like junctions between the myelin loops and the axolemma (Rosenbluth, 1999;Pedraza et al., 2001;Scherer and Arroyo, 2002). These axoglial junctions resemble the SJs present in invertebrates (Banerjee et al., 2006b). Surprisingly, the molecular components identified at the vertebrate paranodal axoglial SJs are also present at the Drosophila neuronal SJs (Banerjee et al., 2006a). KeywordsThe initial insight into the function of the paranodal axoglial SJs came from the phenotypic analysis of the UDP galactose: ceramide galactosyltransferase (CGT) mutants (Coetzee et al., 1996). CGT mutants are deficient in the production of galactocerebroside and sulfatide and display disruption of the axoglial SJs (Coetzee et al., 1996;Dupree et al., 1998Dupree et al., , 1999. Re...

No abstract

No abstract