Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers

Τράκα, Μαρία; Goutebroze, Laurence; Denisenko, Natalia; Bessa, Maria João; Nifli, Artemissia-Phoebe; Havaki, Sophia; Iwakura, Yoichiro; Fukamauchi, Fumihiko; Watanabe, Kazutada; Soliven, Betty; Girault, Jean‐Antoine; Καραγωγεωσ, Δομνα

doi:10.1083/jcb.200305078

Cited by 229 publications

(327 citation statements)

References 50 publications

(97 reference statements)

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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.

159

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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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.

159

158

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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.

207

191

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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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“…It is clear that the localization and retention of voltage-gated Na + (Nav) channels at nodes of Ranvier, and Kv1 channels at juxtaparanodes, requires extrinsic factors derived from myelinating glia (for recent reviews see: Poliak and Peles, 2003;Salzer, 2003). For example, an axonal heterodimer comprised of the cell adhesion molecules caspr2 and TAG-1 interacts with Kv1 channels to restrict their localization to juxtaparanodal domains through trans interactions with glial TAG-1 Traka et al, 2003). Furthermore, the Kv1 channels of mutant mice with aberrant paranodal structure are not restricted to juxtaparanodes (Dupree et al, 1999;Bhat et al, 2001;Boyle et al, 2001), which indicates that the paranode restricts Kv1-channel localization.…”

Section: Introductionmentioning

confidence: 99%

Early events in node of Ranvier formation during myelination and remyelination in the PNS

et al. 2006

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Action potential conduction velocity increases dramatically during early development as axons become myelinated. Integral to this process is the clustering of voltage-gated Na + (Nav) channels at regularly spaced gaps in the myelin sheath called nodes of Ranvier. We show here that some aspects of peripheral node of Ranvier formation are distinct from node formation in the CNS. For example, at CNS nodes, Nav1.2 channels are detected first, but are then replaced by Nav1.6. Similarly, during remyelination in the CNS, Nav1.2 channels are detected at newly forming nodes. By contrast, the earliest Nav-channel clusters detected during developmental myelination in the PNS have Nav1.6. Further, during PNS remyelination, Nav1.6 is detected at new nodes. Finally, we show that accumulation of the cell adhesion molecule neurofascin always precedes Nav channel clustering in the PNS. In most cases axonal neurofascin (NF-186) accumulates first, but occasionally paranodal neurofascin is detected first. We suggest there is heterogeneity in the events leading to Nav channel clustering, indicating that multiple mechanisms might contribute to node of Ranvier formation in the PNS.

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Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers

Cited by 229 publications

References 50 publications

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

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

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

Early events in node of Ranvier formation during myelination and remyelination in the PNS

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