Protein 4.1B associates with both Caspr/paranodin and Caspr2 at paranodes and juxtaparanodes of myelinated fibres

Denisenko-Nehrbass, Natalia; Oguievetskaia, Ksénia; Goutebroze, Laurence; Galvez, Thierry; Yamakawa, Hisashi; Ohara, Osamu; Carnaud, Michèle; Girault, Jean‐Antoine

doi:10.1046/j.1460-9568.2003.02441.x

Cited by 130 publications

(130 citation statements)

References 24 publications

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“…With its intracellular domain, CASPR2 binds to the 4.1B protein (Denisenko-Nehrbass et al, 2003), which is also known as DAL-1 (Differentially expressed in Adenocarcinoma of the Lung). DAL-1 is a member of the protein 4.1 family and acts as a tumor suppressor in meningiomas (Gutmann et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma

et al. 2010

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Genomic translocations have been implicated in cancer.In this study, we performed a screen for genetic translocations in gliomas based on exon-level expression profiles. We identified a translocation in the contactinassociated protein-like 2 (CASPR2) gene, encoding a cell adhesion molecule. CASPR2 mRNA was fused to an expressed sequence tag that likely is part of the nuclear receptor coactivator 1 gene. Despite high mRNA expression levels, no CASPR2 fusion protein was detected. In a set of 25 glioblastomas and 22 oligodendrogliomas, mutation analysis identified two additional samples with genetic alterations in the CASPR2 gene and all three identified genetic alterations are likely to reduce CASPR2 protein expression levels. Methylation of the CASPR2 gene was also observed in gliomas and glioma cell lines. CASPR2-overexpressing cells showed decreased proliferation rates, likely because of an increase in apoptosis. Moreover, high CASPR2 mRNA expression level is positively correlated with survival and is an independent prognostic factor. These results indicate that CASPR2 acts as a tumor suppressor gene in glioma.

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Section: Discussionmentioning

confidence: 99%

The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma

et al. 2010

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“…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]. The present results show that in human neocortical pyramidal cells, Kv1.2 channels are clustered at and colocalize with the adhesion molecule Caspr2 exclusively in the distal domain of the AIS.…”

Section: Discussionmentioning

confidence: 99%

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

Inda

DeFelipe

Muñoz

2006

Proc. Natl. Acad. Sci. U.S.A.

166

158

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The axon initial segment (AIS) of pyramidal cells is a critical region for the generation of action potentials and for the control of pyramidal cell activity. Here we show that Na ؉ and K ؉ voltagegated channels, together with other molecules involved in the localization of ion channels, are distributed asymmetrically in the AIS of pyramidal cells situated in the human temporal neocortex. There is a high density of Na ؉ channels distributed along the length of the AIS together with the associated proteins spectrin ␤IV and ankyrin G. In contrast, Kv1.2 channels are associated with the adhesion molecule Caspr2, and they are mostly localized to the distal region of the AIS. In general, the distal region of the AIS is targeted by the GABAergic axon terminals of chandelier cells, whereas the proximal region is innervated, mostly by other types of GABAergic interneurons. We suggest that this molecular segregation and the consequent regional specialization of the GABAergic input to the AIS of pyramidal cells may have important functional implications for the control of pyramidal cell activity.inhibition ͉ interneurons ͉ neocortex

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“…The cytoskeletal disorganization observed in the NCP1 and CGT mutants suggest that the molecular link between AGJs and the axonal cytoskeleton is important for local arrangement of the cytoskeletal network in Purkinje axons. Other proteins identified as part of the paranodal complex include CNTN and a brain-specific isoform of actin͞spectrin-binding protein, band 4.1B (27). We therefore carried out immunoprecipitation experiments using anti-NCP1 antibodies on membrane-enriched cerebellar lysates from WT and NCP1 and CGT mutants.…”

Section: Axonal Swellings Display Organelle Accumulation and Cytoskelmentioning

confidence: 99%

“…NCP1 is the only identified AGJ axonal protein that contains a cytoplasmic domain. Evidence gathered from biochemical and transgenic mice studies showed that the cytoplasmic domain of NCP1 binds to the actin-spectrin binding protein 4.1B (27,28). There is growing realization that NCP1 mediates AGJ interactions with the axonal cytoskeleton and may participate in axon-glial signaling; however, physiological evidence to support these assumptions remains to be established.…”

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confidence: 99%

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

Garcia-Fresco

Sousa

Pillai

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

121

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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...

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Protein 4.1B associates with both Caspr/paranodin and Caspr2 at paranodes and juxtaparanodes of myelinated fibres

Cited by 130 publications

References 24 publications

The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma

The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma

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

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

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