Paranodin, a Glycoprotein of Neuronal Paranodal Membranes

Menegoz, Mathias; Gaspar, Patricia; Bert, Marc Le; Galvez, Thierry; Burgaya, Ferràn; Palfrey, Clive; Ezan, Pascal; Arnos, Françoise; Girault, Jean‐Antoine

doi:10.1016/s0896-6273(00)80942-3

Cited by 233 publications

(233 citation statements)

References 46 publications

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“…S1 G-J). Because CASPR2 is known to organize voltage-gated ion channels in axonal membrane subdomains in mature neurons (19,27,(34)(35)(36)(37), we asked whether the CASPR2 KD may produce the observed changes in synaptic transmission indirectly by altering the membrane properties of neurons. However, multiple indicators of neuronal excitability, including resting potential, action potential threshold, and spiking frequency in response to fixed current injections, were not affected by the CASPR2 KD, suggesting that the phenotype does not reflect a change in membrane properties (Fig.…”

Section: Caspr2 Kd Globally Decreases Synaptic Strength In a Cell-autmentioning

confidence: 99%

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

Anderson

Galfin

et al. 2012

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

206

179

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Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.dendrite | synaptogenesis A utism spectrum disorders (ASDs) comprise a heterogeneous group of early developmental diseases characterized by repetitive and stereotypic behaviors and impairments in social interactions and language development. ASDs are highly heritable, with recent studies linking mutations at hundreds of genes to ASDs (1-3). These findings raised the fundamental question of how these genes might act in neural circuits without being essential for all brain function. Here, we have attempted to address this question by using a Ca 2+ -imaging screening platform to visualize changes in excitatory network activity following shRNA-mediated knockdown (KD) of prominent cell-adhesion molecules that have been repeatedly implicated in the development of ASDs. We found that molecular manipulation of several ASD candidate genes profoundly influences network activity as monitored by this assay. We observed the biggest effects with the neuronal cell-adhesion molecule contactin-associated protein 2 (CASPR2) that is encoded by the CNTNAP2 gene, leading us to specifically focus on the mechanisms by which this cell-adhesion molecule influences neural circuit development.Mutations in the CNTNAP2 gene have been repeatedly identified in ASD patients (for review, see ref. 4). In addition, mutations in CNTNAP2 also have been linked to epilepsy (5-7), Tourette syndrome (8, 9), schizophrenia (5, 7, 10), attention deficit hyperactivity disorder (ADHD) (11), learning disability (12, 13), and language impairment (14-16). Thus, CNTNAP2 is of central importance for human brain function, as additionally shown by recent in vivo MRI studies in which variations in the CNTNAP2 gene were associated with reduced frontal gray matter and altered functional connectivity (17,18).CASPR2 is a member of the contactin-associated protein family (19). CASPRs are referred to as neurexin IV in Drosophila and are highly homologous to neurexins, which are presynaptic celladhesion molecules (20-23). CASPR2 is best known for its role in mye...

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Section: Caspr2 Kd Globally Decreases Synaptic Strength In a Cell-autmentioning

confidence: 99%

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

Anderson

Galfin

et al. 2012

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

206

179

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“…Within the GFP-OEC transplanted sciatic nerves, nodes of Ranvier were identified by flanking paranodal Caspr immunofluorescence (Menegoz et al, 1997;Rios et al, 2000;Sasaki et al 2006b), which was abundant in these areas (Fig. 2B).…”

Section: Na V 16 Localizes To Nodes Of Regenerated Axons Which Are Rmentioning

confidence: 99%

Myelination and nodal formation of regenerated peripheral nerve fibers following transplantation of acutely prepared olfactory ensheathing cells

et al. 2006

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Transplantation of olfactory ensheathing cells (OECs) into injured spinal cord results in improved functional outcome. Mechanisms suggested to account for this functional improvement include axonal regeneration, remyelination and neuroprotection. OECs transplanted into transected peripheral nerve have been shown to modify peripheral axonal regeneration and functional outcome. However, little is known of the detailed integration of OECs at the transplantation site in peripheral nerve. To address this issue cells populations enriched in OECs were isolated from the olfactory bulbs of adult green fluorescent protein (GFP)-expressing transgenic rats and transplanted into a sciatic nerve crush lesion which transects all axons. Five weeks to six months after transplantation the nerves were studied histologically. GFP-expressing OECs survived in the lesion and distributed longitudinally across the lesion zone. The internodal regions of individual teased fibers distal to the transection site were characterized by GFP expression in the cytoplasmic and nuclear compartments of cells surrounding the axons. Immuno-electron microscopy for GFP indicated that the transplanted OECs formed peripheral type myelin. Immunostaining for sodium channel and Caspr revealed a high density of Na v 1.6 at the newly formed nodes of Ranvier which were flanked by paranodal Caspr staining. These results indicate that transplanted OECs extensively integrate into transected peripheral nerve and form myelin on regenerated peripheral nerve fibers, and that nodes of Ranvier of these axons display proper sodium channel organization.

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“…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).…”

mentioning

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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Paranodin, a Glycoprotein of Neuronal Paranodal Membranes

Cited by 233 publications

References 46 publications

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

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

Myelination and nodal formation of regenerated peripheral nerve fibers following transplantation of acutely prepared olfactory ensheathing cells

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

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