The Expression of TAG-1 in Glial Cells Is Sufficient for the Formation of the Juxtaparanodal Complex and the Phenotypic Rescue of Tag-1 Homozygous Mutants in the CNS

Savvaki, Maria; Theodorakis, Kostas; Zoupi, Lida; Stamatakis, Antonios; Tivodar, Simona; Kyriacou, Kyriacos; Stylianopoulou, Fotini; Καραγωγεωσ, Δομνα

doi:10.1523/jneurosci.2574-10.2010

Cited by 63 publications

(70 citation statements)

References 55 publications

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“…These mice also had impairment of learning and memory (57), which are usually associated with the function of hippocampus. A recent study suggests that only the glial TAG-1 is required for the JXP targeting of Kv1 channels (24), whereas our studies suggest the trans-homophilic interaction of TAG-1 is critical for the placement of Kv1.2 clusters on axonal membranes ( Fig. 3 and supplemental Table SI).…”

Section: Discussioncontrasting

confidence: 72%

“…Caspr2 has a PDZ domain ligand at its C terminus, but deleting PDZ domain-containing proteins, such as PSD-95 (postsynaptic density-95) and/or PSD-93 (postsynaptic density-93), in mice had no effect on the Kv1 JXP targeting (22,23). A recent study suggests that the expression of TAG-1 in myelin cells is sufficient to rescue the JXP complex and phenotypes of TAG-1 knock-out mice (24), questioning the function of axonal TAG-1. Furthermore, deleting other proteins with different functions in mice also disrupted precise Kv1 JXP clustering (25)(26)(27)(28)(29)(30), suggesting that proper functions of many proteins are required.…”

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confidence: 99%

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Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

2011

Journal of Biological Chemistry

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Precise localization of axonal ion channels is crucial for proper electrical and chemical functions of axons. In myelinated axons, Kv1 (Shaker) voltage-gated potassium (Kv) channels are clustered in the juxtaparanodal regions flanking the node of Ranvier. The clustering can be disrupted by deletion of various proteins in mice, including contactin-associated protein-like 2 (Caspr2) and transient axonal glycoprotein-1 (TAG-1), a glycosylphosphatidylinositol-anchored cell adhesion molecule. However, the mechanism and function of Kv1 juxtaparanodal clustering remain unclear. Here, using a new myelin coculture of hippocampal neurons and oligodendrocytes, we report that tyrosine phosphorylation plays a critical role in TAG-1-mediated clustering of axonal Kv1.2 channels. In the coculture, myelin specifically ensheathed axons but not dendrites of hippocampal neurons and clustered endogenous axonal Kv1.2 into internodes. The trans-homophilic interaction of TAG-1 was sufficient to position Kv1.2 clusters on axonal membranes in a neuron/HEK293 coculture. Mutating a tyrosine residue (Tyr 458 ) in the Kv1.2 C terminus or blocking tyrosine phosphorylation disrupted myelin-and TAG-1-mediated clustering of axonal Kv1.2. Furthermore, Kv1.2 voltage dependence and activation threshold were reduced by TAG-1 coexpression. This effect was eliminated by the Tyr 458 mutation or by cholesterol depletion. Taken together, our studies suggest that myelin regulates both trafficking and activity of Kv1 channels along hippocampal axons through TAG-1. Proper subcellular targeting of various Kv channels2 is critical for neuronal excitability and synaptic transmission. Molecular mechanisms underlying polarized axon-dendrite targeting of Kv channels have been extensively studied (1-10). In contrast, channel targeting in distinct membrane domains within axons is much less understood. Most axons in mammals are wrapped by layers of compact lipid membranes from myelinating glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system. Myelinated axons form distinct membrane domains, such as nodes of Ranvier, paranodes, and juxtaparanodal (JXP), and internodal regions (11)(12)(13)(14). In myelinated axons of both CNS and peripheral nervous system, Kv1 channels are clustered into JXP regions, controlling the fidelity of action potential conduction (11,(15)(16)(17).Based on the findings that the JXP targeting of Kv1 channels was largely eliminated in both Caspr2 (contactin-associated protein-like 2) and TAG-1 (transient axonal glycoprotein-1) knock-out mice, it was hypothesized that Caspr2 interacts with TAG-1 and clusters Kv1 channels via a PDZ domain-containing protein (18,19). Whereas Caspr2 is expressed only in neurons, TAG-1 is expressed in both neurons and myelinating glial cells (19 -21). Caspr2 has a PDZ domain ligand at its C terminus, but deleting PDZ domain-containing proteins, such as PSD-95 (postsynaptic density-95) and/or PSD-93 (postsynaptic density-93), in mice had no effect on the K...

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Section: Discussioncontrasting

confidence: 72%

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confidence: 99%

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

2011

Journal of Biological Chemistry

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“…At axo-glial contacts, it has been proposed that the ectodomains of CNTNAP2 and CNTN2 form a cis-complex tethered to the axonal membrane, which in turn recruits a second CNTN2 molecule on the opposing glial membrane to form a bridge spanning the axo-glial cleft (13, 16 -17, 27). However, a transcomplex consisting of an axonal CNTNAP2 and a glial CNTN2 molecule has also been proposed (28). At synaptic contacts, CNTNAP2 and CNTN2 appear to form a trans-complex spanning the synaptic cleft (19).…”

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confidence: 99%

“…CNTNAP2 has been postulated to interact with CNTN2 on account of cell-based assays (13,16,17,19,27,28). To test whether the ectodomains of CNTNAP2 and CNTN2 are sufficient to bind each other directly, we used a solid phase binding assay and showed that CNTNAP2 binds CNTN2 with ϳ3 nM affinity (Fig.…”

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confidence: 99%

Molecular Architecture of Contactin-associated Protein-like 2 (CNTNAP2) and Its Interaction with Contactin 2 (CNTN2)

Reddy

Liu

et al. 2016

Journal of Biological Chemistry

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Contactin-associated protein-like 2 (CNTNAP2) is a large multidomain neuronal adhesion molecule implicated in a number of neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder, intellectual disability, and language delay. We reveal here by electron microscopy that the architecture of CNTNAP2 is composed of a large, medium, and small lobe that flex with respect to each other. Using epitope labeling and fragments, we assign the F58C, L1, and L2 domains to the large lobe, the FBG and L3 domains to the middle lobe, and the L4 domain to the small lobe of the CNTNAP2 molecular envelope. Our data reveal that CNTNAP2 has a very different architecture compared with neurexin 1␣, a fellow member of the neurexin superfamily and a prototype, suggesting that CNTNAP2 uses a different strategy to integrate into the synaptic protein network. We show that the ectodomains of CNTNAP2 and contactin 2 (CNTN2) bind directly and specifically, with low nanomolar affinity. We show further that mutations in CNTNAP2 implicated in autism spectrum disorder are not segregated but are distributed over the whole ectodomain. The molecular shape and dimensions of CNTNAP2 place constraints on how CNTNAP2 integrates in the cleft of axo-glial and neuronal contact sites and how it functions as an organizing and adhesive molecule.

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“…We have shown that homozygous mutants display a series of behavioral alterations such as learning and memory defects as well as motor coordination and balance abnormalities, resulting from the molecular disorganization of myelinated fibers (Traka et al, 2003;Savvaki et al, 2008Savvaki et al, , 2010. When the juxtaparanodal domain organization of myelinated fibers was rescued in vivo, learning and memory defects that are dependent on hippocampal function were also rescued (Savvaki et al, 2010). Our present analysis reveals that Tag1 −/− mice are able to smell volatile and nonvolatile odors in the buried food and social interaction tests respectively, but show a profound disruption in odor discrimination and long-term social memory formation.…”

Section: Discussionmentioning

confidence: 99%

TAG-1 deficiency results in olfactory dysfunction due to impaired migration of mitral cells

et al. 2015

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The olfactory system provides mammals with the abilities to investigate, communicate and interact with their environment. These functions are achieved through a finely organized circuit starting from the nasal cavity, passing through the olfactory bulb and ending in various cortical areas. We show that the absence of transient axonal glycoprotein-1 (Tag1)/contactin-2 (Cntn2) in mice results in a significant and selective defect in the number of the main projection neurons in the olfactory bulb, namely the mitral cells. A subpopulation of these projection neurons is reduced in Tag1-deficient mice as a result of impaired migration. We demonstrate that the detected alterations in the number of mitral cells are well correlated with diminished odor discrimination ability and social long-term memory formation. Reduced neuronal activation in the olfactory bulb and the corresponding olfactory cortex suggest that Tag1 is crucial for the olfactory circuit formation in mice. Our results underpin the significance of a numerical defect in the mitral cell layer in the processing and integration of odorant information and subsequently in animal behavior.

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The Expression of TAG-1 in Glial Cells Is Sufficient for the Formation of the Juxtaparanodal Complex and the Phenotypic Rescue of Tag-1 Homozygous Mutants in the CNS

Cited by 63 publications

References 55 publications

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

Molecular Architecture of Contactin-associated Protein-like 2 (CNTNAP2) and Its Interaction with Contactin 2 (CNTN2)

TAG-1 deficiency results in olfactory dysfunction due to impaired migration of mitral cells

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