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At least 19 recordsLinked to original sources

PubMed2000

Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination.

Specialized paranodal junctions form between the axon and the closely apposed paranodal loops of myelinating glia. They are interposed between sodium channels at the nodes of Ranvier and potassium channels in the juxtaparanodal regions; their precise function and molecular composition have been elusive. We previously reported that Caspr (contactin-associated protein) is a major axonal constituent of these junctions (Einheber et al., 1997). We now report that contactin colocalizes and forms a cis complex with Caspr in the paranodes and juxtamesaxon. These proteins coextract and coprecipitate from neurons, myelinating cultures, and myelin preparations enriched in junctional markers; they fractionate on sucrose gradients as a high-molecular-weight complex, suggesting that other proteins may also be associated with this complex. Neurons express two contactin isoforms that differ in their extent of glycosylation: a lower-molecular-weight phosphatidylinositol phospholipase C (PI-PLC)-resistant form is associated specifically with Caspr in the paranodes, whereas a higher-molecular-weight form of contactin, not associated with Caspr, is present in central nodes of Ranvier. These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. Treatment of myelinating cocultures of Schwann cells and neurons with RPTPbeta-Fc, a soluble construct containing the carbonic anhydrase domain of the receptor protein tyrosine phosphatase beta (RPTPbeta), a potential glial receptor for contactin, blocks the localization of the Caspr/contactin complex to the paranodes. These results strongly suggest that a preformed complex of Caspr and contactin is targeted to the paranodal junctions via extracellular interactions with myelinating glia.

Animals↗

PubMed2004

Drosophila contactin, a homolog of vertebrate contactin, is required for septate junction organization and paracellular barrier function.

Septate junctions (SJs) in epithelial and neuronal cells play an important role in the formation and maintenance of charge and size selective barriers. They form the basis for the ensheathment of nerve fibers in Drosophila and for the attachment of myelin loops to axonal surface in vertebrates. The cell-adhesion molecules NRX IV/Caspr/Paranodin (NCP1), contactin and Neurofascin-155 (NF-155) are all present at the vertebrate axo-glial SJs. Mutational analyses have shown that vertebrate NCP1 and its Drosophila homolog, Neurexin IV (NRX IV) are required for the formation of SJs. In this study, we report the genetic, molecular and biochemical characterization of the Drosophila homolog of vertebrate contactin, CONT. Ultrastructural and dye-exclusion analyses of Cont mutant embryos show that CONT is required for organization of SJs and paracellular barrier function. We show that CONT, Neuroglian (NRG) (Drosophila homolog of NF-155) and NRX IV are interdependent for their SJ localization and these proteins form a tripartite complex. Hence, our data provide evidence that the organization of SJs is dependent on the interactions between these highly conserved cell-adhesion molecules.

Animals↗

PubMed2006

Contactin is expressed in human astrocytic gliomas and mediates repulsive effects.

Contactin is a cell surface adhesion molecule that is normally expressed by neurons and oligodendrocytes. Particularly high levels of contactin are present during brain development. Using subtractive cloning, we identified contactin transcripts as overexpressed in glioblastomas compared with normal brain. We confirmed contactin overexpression in glioblastomas at the protein level, and localized contactin to the surface of glial fibrillary acidic protein (GFAP)-expressing glioblastoma cells. In contrast, normal astrocytes did not express contactin. Analyzing different types of astrocytic tumors, we detected an association between increasing malignancy grade and contactin expression. Functionally, contactin had repellent effects on glioma cells in vitro, as demonstrated by adhesion and migration assays. Overexpression of contactin by transfection into glioblastoma cells did not alter the proliferation rate or adhesion to various extracellular matrix proteins as well as adhesion to cells expressing the specific contactin ligand the protein tyrosine phosphatase zeta (PTPzeta). Our findings suggest that contactin has repellent effects on glioma cells to which it is presented as a ligand, but it does not alter the proliferative or adhesive capacities of cells that overexpress the molecule. The repulsive properties of contactin may be a key factor in glioma disaggregation, and may contribute to the diffuse infiltration pattern characteristic of glioma cells in human brain.

Astrocytes↗

PubMed1994

Molecular cloning and in situ localization of the human contactin gene (CNTN1) on chromosome 12q11-q12.

Chick contactin/F11 (also known as F3 in mouse) is a neuronal cell adhesion molecule of the immunoglobulin (Ig) gene family that is implicated in playing a role in the formation of axon connections in the developing nervous system. In human brain, contactin was first identified by amino terminal and peptide sequencing of the lentil-lectin-binding glycoprotein Gp135. We now report the isolation and characterization of cDNA clones encoding human contactin. Human contactin is composed of six C2 Ig-domains and four fibronectin type III (FNIII) repeats and is anchored to the membrane via a glycosyl phosphatidylinositol moiety, as shown by PI-PLC treatment of cells transfected with contactin cDNA and metabolic labeling with [3H]-ethanolamine. At the amino acid level, h-contactin is 78% identical to chick contactin/F11 and 94% to mouse F3. Independent cDNAs encoding two putative contactin isoforms were isolated and sequenced: h-contactin 1 cDNA encodes a protein with the amino-terminal sequence of purified Gp135, while the putative h-contactin 2 gene has a deletion of 33 nucleotides that predicts a protein with a shortened amino terminus. Northern analysis with a probe common for both isoforms detects one mRNA species of approximately 6.6 kb in adult human brain. Fluorescence in situ hybridization maps the gene for human contactin to human chromosome 12q11-q12. The h-contactin gene locus is thus in close proximity to homeobox 3, integrin subunit alpha 5, several proto-oncogene genes, a chromosomal breakpoint associated with various tumors, and the gene locus for Stickler syndrome. The cloning of human contactin now permits the study of its role in disorders of the human nervous system.

Adult↗

PubMed2005

Repulsive guidance of axons of spinal sensory neurons in Xenopus laevis embryos: roles of Contactin and notochord-derived chondroitin sulfate proteoglycans.

An immunoglobulin superfamily neuronal adhesion molecule, Contactin, has been implicated in axon guidance of spinal sensory neurons in Xenopus embryos. To identify the guidance signaling molecules that Contactin recognizes in tailbud embryos, an in situ binding assay was performed using recombinant Contactin-alkaline phosphatase fusion protein (Contactin-AP) as a probe. In the assay of whole-mount or sectioned embryos, Contactin-AP specifically bound to the notochord and its proximal regions. This binding was completely blocked by either digestion of embryo sections with chondroitinase ABC or pretreatment of Contactin-AP with chondroitin sulfate A. When the spinal cord and the notochord explants were co-cultured in collagen gel, growing Contactin-positive spinal axons were repelled by notochord-derived repulsive activity. This repulsive activity was abolished by the addition of either a monoclonal anti-Contactin antibody, chondroitin sulfate A or chondroitinase ABC to the culture medium. An antibody that recognizes chondroitin sulfate A and C labeled immunohistochemically the notochord in embryo sections and the collagen gel matrix around the cultured notochord explant. Addition of chondroitinase ABC into the culture eliminated the immunoreactivity in the gel matrix. These results suggest that the notochord-derived chondroitin sulfate proteoglycan acts as a repulsive signaling molecule that is recognized by Contactin on spinal sensory axons.

Animals↗

PubMed2000

An essential role of the neuronal cell adhesion molecule contactin in development of the Xenopus primary sensory system.

Contactin is a glycosylphosphatidylinositol-anchored immunoglobulin-like neuronal cell adhesion molecule that has been implicated in cellular interaction during development of the vertebrate central nervous system. Here we report evidence for an essential role of contactin in development of the Xenopus nervous system. Contactin mRNA is detectable by in situ hybridization in subsets of neurons in the brain, primary sensory neurons in the spinal cord, and cells along the trigeminal nerves of tailbud embryos. Contactin immunoreactivities preferentially distribute on axon tracts of the brain, the spinal cord, and the trigeminal sensory nerves. Most prominently, cell bodies and peripheral and spinal axons of primary sensory neurons, Rohon-Beard (RB) cells, are strongly contactin positive. Injection of the contactin overexpression vector into one blastomere of two-cell stage embryos leads to misdirected elongation of the peripheral axons of RB neurons in the injected half. Overexpression of antisense transcript causes depletion of contactin mRNA accumulation and abnormal development of RB neurons. In 52.3% of the injected embryos, RB neurons decrease in number and their peripheral axons in dorsal lateral tracts are defasciculated. These results demonstrate that contactin plays an essential role in development of the Xenopus primary sensory system.

Animals↗

PubMed2005

Alterations of arcuate nucleus neuropeptidergic development in contactin-deficient mice: comparison with anorexia and food-deprived mice.

A mutation in the Contactin-1 gene results in an ataxic and anorectic phenotype that is apparent by postnatal day 10 and lethal by postnatal day 19 [Berglund et al. (1999) Neuron 24, 739-750]. The resemblance of this phenotype with the anorexia (anx/anx) mouse mutation prompted us to investigate the hypothalamic neurochemistry of Contactin knock-out (KO) mice. Contactin was expressed in the hypothalamic neuropil of wild-type (WT) but not Contactin KO mice. In the KO condition, neuropeptide Y (NPY) and agouti-related protein (AgRP) immunoreactivity (IR) accumulated in the somata of arcuate nucleus neurons, whereas IR for these neuropeptides as well as for alpha-melanocyte-stimulating hormone (alpha-MSH) decreased in the corresponding axon projections. These changes in the pattern of neuropeptide expression in the Contactin-deficient hypothalamus were similar but more pronounced than those found in anx/anx mice. Increased levels of NPY and AgRP and decreased concentrations of pro-opiomelanocortin mRNA in arcuate neurons accompanied these changes. In relating these alterations a 24-h food deprivation period, we observed in 3-week-old WT mice an elevation of NPY- and AgRP-IR in the perikarya of arcuate neurons without notable reduction of NPY- or AgRP-IR in nerve fibers, suggesting that the decrease of arcuate projections can be associated with postnatal anorectic phenotype. Our data implicate Contactin in the postnatal development of the NPY/AgRP and alpha-MSH arcuate neurons and suggest that similar to anx/anx mutant mice, compromised orexigenic signaling via NPY/AgRP neurons may contribute to reduced food intake by the Contactin-mutant animals.

Agouti-Related Protein↗

PubMed2006

Knockdown of contactin-1 expression suppresses invasion and metastasis of lung adenocarcinoma.

Numerous genetic changes are associated with cancer cell metastasis and invasion. In search for key regulators of invasion and metastasis, a panel of lung cancer cell lines with different invasive ability was screened. The gene for contactin-1 was found to play an essential role in tumor invasion and metastasis. Suppression of contactin-1 expression abolished the ability of lung adenocarcinoma cells to invade Matrigel in vitro as well as the polymerization of filamentous-actin and the formation of focal adhesion structures. Furthermore, knockdown of contactin-1 resulted in extensive inhibition of tumor metastasis and in increased survival in an animal model. RhoA but not Cdc42 or Rac1 was found to serve a critical role in contactin-1-mediated invasion and metastasis. Contactin-1-specific RNA interference resulted in loss of metastatic and invasive capacity in both in vitro and in vivo models. This loss was overturned by constitutive expression of the active form of RhoA. Contactin-1 was differentially expressed in tumor tissues, and its expression correlated with tumor stage, lymph node metastasis, and patient survival. Contactin-1 is proposed to function importantly in the invasion and metastasis of lung adenocarcinoma cells via RhoA-mediated mechanisms.

Actins↗

PubMed1994

Identification and characterization of the human cell adhesion molecule contactin.

We have prepared a monoclonal antibody, Neuro-1, that recognizes the human homolog of the chicken contactin/F11 and mouse F3 cell adhesion molecules. The Neuro-1 antigen, structurally characterized as a 135 kDa glycosylphosphatidylinositol-linked glycoprotein, was immunoaffinity purified and partially sequenced. Comparison of an internal peptide sequence to that predicted from the chicken contactin/F11, mouse F3 and human contactin (reported herein) cDNA sequence identifies the Neuro-1 antigen as human contactin. Moreover, a polyclonal antisera generated against the purified Neuro-1 antigen was immunoreactive with a fragment of human contactin expressed in bacteria. The complete coding and deduced amino acid sequences of human contactin were determined and are 86% and 95% identical to the respective mouse F3 sequences. Structural features shared with contactin/F11/F3 include six immunoglobulin type C2 and four fibronectin type III-like domains, multiple sites for asn-linked glycosylation and a COOH-terminal signal peptide presumably removed during the generation of a phosphatidylinositol cell surface linkage. The potential for glycosylation and GPI-linkage is also consistent with protein chemical studies of human contactin. Contactin mRNA expression was characterized using Northern blot analyses of human tissues and cell lines. High level expression of a single contactin transcript in adult brain, and low level expression of multiple transcripts in lung, pancreas, kidney and skeletal muscle are observed. Highly expressed multiple transcripts, similar in pattern to that of pancreas, lung, kidney and skeletal muscle, are also observed in human neuroblastoma and retinoblastoma cell lines.

Amino Acid Sequence↗

PubMed2002

Contactin supports synaptic plasticity associated with hippocampal long-term depression but not potentiation.

BACKGROUND: Changes in synaptic efficacy are believed to mediate the processes of learning and memory formation. Accumulating evidence implicates cell adhesion molecules in activity-dependent synaptic modifications associated with long-term potentiation (LTP); however, there is no precedence for the selective role of this molecule class in long-term depression (LTD). The mechanisms that modulate these processes still remain unclear. RESULTS: We report a novel role for glycosylphosphatidyl inositol (GPI)-anchored contactin in hippocampal CA1 synaptic plasticity. Contactin selectively supports paired-pulse facilitation (PPF) and NMDA (N-methyl-D-aspartate) receptor-dependent LTD but is not required for synaptic morphology, basal transmission, or LTP. Molecular analyses indicate that contactin is essential for the membrane and synaptic targeting of the contactin-associated protein (Caspr/paranodin) and for the proper distribution of a presumptive ligand, receptor protein tyrosine phosphatase beta (RPTPbeta)/phosphacan. CONCLUSIONS: These results indicate that contactin plays a selective role in synaptic plasticity and identify PPF and LTD, but not LTP, as contactin-dependent processes. Engagement of the contactin-Caspr complex with RPTPbeta may thus regulate cell-cell interactions contributing to specific synaptic plasticity forms.

Animals↗

PubMed1996

cDNA cloning and expression of the Xenopus homologue of the neural adhesion molecule, contactin (F3/F11).

Contactin (F3/F11) is an immunoglobulin superfamily cell surface glycoprotein predominantly expressed in the nervous system. To examine the structure and tissue distribution of Xenopus contactin, a cDNA clone was isolated based on the amino acid sequences conserved among chicken and mammalian contactin proteins. The conceptual translate of the cDNA consists of 1005 amino acid residues that have 70% identity to those of chicken and mammalian contactin. Northern blot hybridization using a labeled cDNA fragment revealed specific expression of 6.5 kb mRNA in the brain. Monoclonal and polyclonal antibodies prepared to the recombinant Xenopus contactin peptides detected a single 135 kD band on Western blots of the brain and spinal cord extracts. Differential extraction and phosphatidylinositol-specific phospholipase C (PI-PLC) digestion experiments showed that the immunoreactive 135 kD proteins bind, at least in part to the membrane by GPI anchor. On brain tissue sections, strong contactin immunoreactivities were detected on nerve fibers of a subset of cerebral and cerebellar neurons. These results suggest that the basic structure and tissue distribution of Xenopus contactin are similar to those in other vertebrates.

Amino Acid Sequence↗

PubMed2001

Contactin associates with Na+ channels and increases their functional expression.

Contactin (also known as F3, F11) is a surface glycoprotein that has significant homology with the beta2 subunit of voltage-gated Na(+) channels. Contactin and Na(+) channels can be reciprocally coimmunoprecipitated from brain homogenates, indicating association within a complex. Cells cotransfected with Na(+) channel Na(v)1.2alpha and beta1 subunits and contactin have threefold to fourfold higher peak Na(+) currents than cells with Na(v)1.2alpha alone, Na(v)1.2/beta1, Na(v)1.2/contactin, or Na(v)1.2/beta1/beta2. These cells also have a correspondingly higher saxitoxin binding, suggesting an increased Na(+) channel surface membrane density. Coimmunoprecipitation of different subunits from cell lines shows that contactin interacts specifically with the beta1 subunit. In the PNS, immunocytochemical studies show a transient colocalization of contactin and Na(+) channels at new nodes of Ranvier forming during remyelination. In the CNS, there is a particularly high level of colocalization of Na(+) channels and contactin at nodes both during development and in the adult. Contactin may thus significantly influence the functional expression and distribution of Na(+) channels in neurons.

Animals↗

PubMed2003

Caspr regulates the processing of contactin and inhibits its binding to neurofascin.

Three cell adhesion molecules are present at the axoglial junctions that form between the axon and myelinating glia on either side of nodes of Ranvier. These include an axonal complex of contacin-associated protein (Caspr) and contactin, which was proposed to bind NF155, an isoform of neurofascin located on the glial paranodal loops. Here, we show that NF155 binds directly to contactin and that surprisingly, coexpression of Caspr inhibits this interaction. This inhibition reflects the association of Caspr with contactin during biosynthesis and the resulting expression of a low molecular weight (LMw), endoglycosidase H-sensitive isoform of contactin at the cell membrane, which remains associated with Caspr but is unable to bind NF155. Accordingly, deletion of Caspr in mice by gene targeting results in a shift from the LMw- to a HMw-contactin glycoform. These results demonstrate that Caspr regulates the intracellular processing and transport of contactin to the cell surface, thereby affecting its ability to interact with other cell adhesion molecules.

Animals↗

PubMed2004

Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface.

The upregulation of voltage-gated sodium channel Na(v)1.3 has been linked to hyperexcitability of axotomized dorsal root ganglion (DRG) neurons, which underlies neuropathic pain. However, factors that regulate delivery of Na(v)1.3 to the cell surface are not known. Contactin/F3, a cell adhesion molecule, has been shown to interact with and enhance surface expression of sodium channels Na(v)1.2 and Na(v)1.9. In this study we show that contactin coimmunoprecipitates with Na(v)1.3 from postnatal day 0 rat brain where this channel is abundant, and from human embryonic kidney (HEK) 293 cells stably transfected with Na(v)1.3 (HEK-Na(v)1.3). Purified GST fusion proteins of the N and C termini of Na(v)1.3 pull down contactin from lysates of transfected HEK 293 cells. Transfection of HEK-Na(v)1.3 cells with contactin increases the amplitude of the current threefold without changing the biophysical properties of the channel. Enzymatic removal of contactin from the cell surface of cotransfected cells does not reduce the elevated levels of the Na(v)1.3 current. Finally, we show that, similar to Na(v)1.3, contactin is upregulated in axotomized DRG neurons and accumulates within the neuroma of transected sciatic nerve. We propose that the upregulation of contactin and its colocalization with Na(v)1.3 in axotomized DRG neurons may contribute to the hyper-excitablity of the injured neurons.

Animals↗

PubMed1995

The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin.

Receptor-type protein tyrosine phosphatase beta (RPTP beta) is expressed in the developing nervous system and contains a carbonic anhydrase (CAH) domain as well as a fibronectin type III repeat in its extracellular domain. Fusion proteins containing these domains were used to search for ligands of RPTP beta. The CAH domain bound specifically to a 140 kDa protein expressed on the surface of neuronal cells. Expression cloning in COS7 cells revealed that this protein is contactin, a GPI membrane-anchored neuronal cell recognition molecule. The CAH domain of RPTP beta induced cell adhesion and neurite growth of primary tectal neurons, and differentiation of neuroblastoma cells. These responses were blocked by antibodies against contactin, demonstrating that contactin is a neuronal receptor for RPTP beta. These experiments show that an individual domain of RPTP beta acts as a functional ligand for the neuronal receptor contactin. The interaction between contactin and RPTP beta may generate unidirectional or bidirectional signals during neural development.

Amino Acid Sequence↗

PubMed1999

Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression.

Axon guidance and target recognition depend on neuronal cell surface receptors that recognize and elicit selective growth cone responses to guidance cues in the environment. Contactin, a cell adhesion/recognition molecule of the immunoglobulin gene superfamily, regulates axon growth and fasciculation in vitro, but its role in vivo is unknown. To assess its function in the developing nervous system, we have ablated contactin gene expression in mice. Contactin-/- mutants displayed a severe ataxic phenotype consistent with defects in the cerebellum and survived only until postnatal day 18. Analysis of the contactin-/- mutant cerebellum revealed defects in granule cell axon guidance and in dendritic projections from granule and Golgi cells. These results demonstrate that contactin controls axonal and dendritic interactions of cerebellar interneurons and contributes to cerebellar microorganization.

Animals↗

PubMed2001

Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve.

Rapid nerve impulse conduction depends on specialized membrane domains in myelinated nerve, the node of Ranvier, the paranode, and the myelinated internodal region. We report that GPI-linked contactin enables the formation of the paranodal septate-like axo-glial junctions in myelinated peripheral nerve. Contactin clusters at the paranodal axolemma during Schwann cell myelination. Ablation of contactin in mutant mice disrupts junctional attachment at the paranode and reduces nerve conduction velocity 3-fold. The mutation impedes intracellular transport and surface expression of Caspr and leaves NF155 on apposing paranodal myelin disengaged. The contactin mutation does not affect sodium channel clustering at the nodes of Ranvier but alters the location of the Shaker-type Kv1.1 and Kv1.2 potassium channels. Thus, contactin is a crucial part in the machinery that controls junctional attachment at the paranode and ultimately the physiology of myelinated nerve.

Aging↗

PubMed1997

Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions.

Receptor protein tyrosine phosphatase beta (RPTPbeta) expressed on the surface of glial cells binds to the glycosylphosphatidylinositol (GPI)-anchored recognition molecule contactin on neuronal cells leading to neurite outgrowth. We describe the cloning of a novel contactin-associated transmembrane receptor (p190/Caspr) containing a mosaic of domains implicated in protein-protein interactions. The extracellular domain of Caspr contains a neurophilin/coagulation factor homology domain, a region related to fibrinogen beta/gamma, epidermal growth factor-like repeats, neurexin motifs as well as unique PGY repeats found in a molluscan adhesive protein. The cytoplasmic domain of Caspr contains a proline-rich sequence capable of binding to a subclass of SH3 domains of signaling molecules. Caspr and contactin exist as a complex in rat brain and are bound to each other by means of lateral (cis) interactions in the plasma membrane. We propose that Caspr may function as a signaling component of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. The binding of RPTPbeta to the contactin-Caspr complex could provide a mechanism for cell-cell communication between glial cells and neurons during development.

Amino Acid Sequence↗