Contactins: A family of immunoglobulin-related cell adhesion molecules that are involved in NERVOUS SYSTEM patterning.Oligodendroglia: A class of large neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal (not the same as SATELLITE CELLS, PERINEURONAL of GANGLIA) according to their location. They form the insulating MYELIN SHEATH of axons in the central nervous system.Myelin Sheath: The lipid-rich sheath surrounding AXONS in both the CENTRAL NERVOUS SYSTEMS and PERIPHERAL NERVOUS SYSTEM. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (SCHWANN CELLS in the peripheral and OLIGODENDROGLIA in the central nervous system). Deterioration of the sheath in DEMYELINATING DISEASES is a serious clinical problem.Demyelinating Diseases: Diseases characterized by loss or dysfunction of myelin in the central or peripheral nervous system.Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body.Laminin: Large, noncollagenous glycoprotein with antigenic properties. It is localized in the basement membrane lamina lucida and functions to bind epithelial cells to the basement membrane. Evidence suggests that the protein plays a role in tumor invasion.Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.Schwann Cells: Neuroglial cells of the peripheral nervous system which form the insulating myelin sheaths of peripheral axons.Contactin 1: A contactin subtype that is predominantly expressed in the CEREBELLUM; HIPPOCAMPUS; NEOCORTEX; and HYPOTHALAMUS.Cell Adhesion Molecules, Neuronal: Surface ligands that mediate cell-to-cell adhesion and function in the assembly and interconnection of the vertebrate nervous system. These molecules promote cell adhesion via a homophilic mechanism. These are not to be confused with NEURAL CELL ADHESION MOLECULES, now known to be expressed in a variety of tissues and cell types in addition to nervous tissue.Contactin 2: A contactin subtype that plays a role in axon outgrowth, axon fasciculation, and neuronal migration.Nerve Tissue ProteinsMutism: The inability to generate oral-verbal expression, despite normal comprehension of speech. This may be associated with BRAIN DISEASES or MENTAL DISORDERS. Organic mutism may be associated with damage to the FRONTAL LOBE; BRAIN STEM; THALAMUS; and CEREBELLUM. Selective mutism is a psychological condition that usually affects children characterized by continuous refusal to speak in social situations by a child who is able and willing to speak to selected persons. Kussmal aphasia refers to mutism in psychosis. (From Fortschr Neurol Psychiatr 1994; 62(9):337-44)Child Development Disorders, Pervasive: Severe distortions in the development of many basic psychological functions that are not normal for any stage in development. These distortions are manifested in sustained social impairment, speech abnormalities, and peculiar motor movements.Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the ANTIGEN (or a very similar shape) that induced their synthesis in cells of the lymphoid series (especially PLASMA CELLS).Antibody Specificity: The property of antibodies which enables them to react with some ANTIGENIC DETERMINANTS and not with others. Specificity is dependent on chemical composition, physical forces, and molecular structure at the binding site.Antibodies, Viral: Immunoglobulins produced in response to VIRAL ANTIGENS.Antibodies, Monoclonal: Antibodies produced by a single clone of cells.Antibodies, Bacterial: Immunoglobulins produced in a response to BACTERIAL ANTIGENS.Polyradiculoneuropathy, Chronic Inflammatory Demyelinating: A slowly progressive autoimmune demyelinating disease of peripheral nerves and nerve roots. Clinical manifestations include weakness and sensory loss in the extremities and enlargement of peripheral nerves. The course may be relapsing-remitting or demonstrate a step-wise progression. Protein is usually elevated in the spinal fluid and cranial nerves are typically spared. GUILLAIN-BARRE SYNDROME features a relatively rapid progression of disease which distinguishes it from this condition. (Adams et al., Principles of Neurology, 6th ed, p1337)Polyradiculoneuropathy: Diseases characterized by injury or dysfunction involving multiple peripheral nerves and nerve roots. The process may primarily affect myelin or nerve axons. Two of the more common demyelinating forms are acute inflammatory polyradiculopathy (GUILLAIN-BARRE SYNDROME) and POLYRADICULONEUROPATHY, CHRONIC INFLAMMATORY DEMYELINATING. Polyradiculoneuritis refers to inflammation of multiple peripheral nerves and spinal nerve roots.Guillain-Barre Syndrome: An acute inflammatory autoimmune neuritis caused by T cell- mediated cellular immune response directed towards peripheral myelin. Demyelination occurs in peripheral nerves and nerve roots. The process is often preceded by a viral or bacterial infection, surgery, immunization, lymphoma, or exposure to toxins. Common clinical manifestations include progressive weakness, loss of sensation, and loss of deep tendon reflexes. Weakness of respiratory muscles and autonomic dysfunction may occur. (From Adams et al., Principles of Neurology, 6th ed, pp1312-1314)Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of CEREBELLAR DISEASES, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of PARKINSON DISEASE.Plasma Exchange: Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (PPF), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions.Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system.Goats: Any of numerous agile, hollow-horned RUMINANTS of the genus Capra, in the family Bovidae, closely related to the SHEEP.Protein Tyrosine Phosphatases: An enzyme group that specifically dephosphorylates phosphotyrosyl residues in selected proteins. Together with PROTEIN-TYROSINE KINASE, it regulates tyrosine phosphorylation and dephosphorylation in cellular signal transduction and may play a role in cell growth control and carcinogenesis.Protein Tyrosine Phosphatase, Non-Receptor Type 1: A subtype of non-receptor protein tyrosine phosphatases that includes two distinctive targeting motifs; an N-terminal motif specific for the INSULIN RECEPTOR, and a C-terminal motif specific for the SH3 domain containing proteins. This subtype includes a hydrophobic domain which localizes it to the ENDOPLASMIC RETICULUM.Receptor-Like Protein Tyrosine Phosphatases: A subcategory of protein tyrosine phosphatases that are bound to the cell membrane. They contain cytoplasmic tyrosine phosphatase domains and extracellular protein domains that may play a role in cell-cell interactions by interacting with EXTRACELLULAR MATRIX components. They are considered receptor-like proteins in that they appear to lack specific ligands.

Analysis of receptor binding by the channel-forming toxin aerolysin using surface plasmon resonance. (1/114)

Aerolysin is a channel-forming bacterial toxin that binds to glycosylphosphatidylinositol (GPI) anchors on host cell-surface structures. The nature of the receptors and the location of the receptor-binding sites on the toxin molecule were investigated using surface plasmon resonance. Aerolysin bound to the GPI-anchored proteins Thy-1, variant surface glycoprotein, and contactin with similar rate constants and affinities. Enzymatic removal of N-linked sugars from Thy-1 did not affect toxin binding, indicating that these sugars are not involved in the high affinity interaction with aerolysin. Aerolysin is a bilobal protein, and both lobes were shown to be required for optimal binding. The large lobe by itself bound Thy-1 with an affinity that was at least 10-fold weaker than that of the whole toxin, whereas the small lobe bound the GPI-anchored protein at least 1000-fold more weakly than the intact toxin. Mutation analyses provided further evidence that both lobes were involved in GPI anchor binding, with certain single amino acid substitutions in either domain leading to reductions in affinity of as much as 100-fold. A variant with single amino acid substitutions in both lobes of the protein was completely unable to bind the receptor. The membrane protein glycophorin, which is heavily glycosylated but not GPI-anchored, bound weakly to immobilized proaerolysin, suggesting that interactions with cell-surface carbohydrate structures other than GPI anchors may partially mediate toxin binding to host cells.  (+info)

Functional interactions of the immunoglobulin superfamily member F11 are differentially regulated by the extracellular matrix proteins tenascin-R and tenascin-C. (2/114)

The axon-associated protein F11 is a GPI-anchored member of the immunoglobulin superfamily that promotes axon outgrowth and that shows a complex binding pattern toward multiple cell surface and extracellular matrix proteins including tenascin-R and tenascin-C. In this study, we demonstrate that tenascin-R and tenascin-C differentially modulate cell adhesion and neurite outgrowth of tectal cells on F11. While soluble tenascin-R increases the number of attached cells and the percentage of cells with neurites on immobilized F11, tenascin-C stimulates cell attachment to a similar extent but decreases neurite outgrowth. The cellular receptor interacting with F11 has been previously identified as NrCAM; however, in the presence of tenascin-R or tenascin-C cell attachment and neurite extension are independent of NrCAM. Antibody perturbation experiments indicate that beta(1) integrins instead of NrCAM function as receptor for neurite outgrowth of tectal cells on an F11.TN-R complex. Cellular binding assays support the possibility that the interaction of F11 to NrCAM is blocked in the presence of tenascin-R and tenascin-C. Furthermore, a sandwich binding assay demonstrates that tenascin-R and tenascin-C are able to form larger molecular complexes and to link F11 polypeptides by forming a molecular bridge. These results suggest that the molecular interactions of F11 might be regulated by the presence of tenascin-R and tenascin-C.  (+info)

NrCAM, cerebellar granule cell receptor for the neuronal adhesion molecule F3, displays an actin-dependent mobility in growth cones. (3/114)

The neuronal adhesion glycoprotein F3 is a multifunctional molecule of the immunoglobulin superfamily that displays heterophilic binding activities. In the present study, NrCAM was identified as the functional receptor mediating the inhibitory effect of F3 on axonal elongation from cerebellar granule cells. F3Fc-conjugated microspheres binding to neuronal growth cones resulted from heterophilic interaction with NrCAM but not with L1. Time-lapse video-microscopy indicated that F3Fc beads bind at the leading edge and move retrogradely to reach the base of the growth cone within a lapse of 30-60 seconds. Such velocity (5.7 microm/minute) is consistent with a coupling between F3 receptors and the retrograde flow of actin filaments. When actin filaments were disrupted by cytochalasin B, the F3Fc beads remained immobile at the leading edge. The retrograde mobility appeared to be dependent on NrCAM clustering since it was induced upon binding with cross-linked but not dimeric F3Fc chimera. These data indicate that F3 may control growth cone motility by modulating the linkage of its receptor, NrCAM, to the cytoskeleton. They provide further insights into the mechanisms by which GPI-anchored adhesion molecules may exert an inhibitory effect on axonal elongation.  (+info)

Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities. (4/114)

Mutations in the gene for neural cell adhesion molecule L1 (L1CAM) result in a debilitating X-linked congenital disorder of brain development. At the neuronal cell surface L1 may interact with a variety of different molecules including itself and two other CAMs of the immunoglobulin superfamily, axonin-1 and F11. However, whether all of these interactions are relevant to normal or abnormal development has not been determined. Over one-third of patient mutations are single amino acid changes distributed across 10 extracellular L1 domains. We have studied the effects of 12 missense mutations on binding to L1, axonin-1 and F11 and shown for the first time that whereas many mutations affect all three interactions, others affect homophilic or heterophilic binding alone. Patient pathology is therefore due to different types of L1 malfunction. The nature and functional consequence of mutation is also reflected in the severity of the resultant phenotype with structural mutations likely to affect more than one binding activity and result in early mortality. Moreover, the data indicate that several extracellular domains of L1 are required for homophilic and heterophilic interactions.  (+info)

Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination. (5/114)

In many cell types, glycosylphosphatidylinositol (GPI)-anchored proteins are sequestered in detergent-resistant membrane rafts. These are plasma membrane microdomains enriched in glycosphingolipids and cholesterol and are suggested to be platforms for cell signaling. Concomitant with the synthesis of myelin glycosphingolipids, maturing oligodendrocytes progressively associate GPI-anchored proteins, including the adhesion molecules NCAM 120 and F3, in rafts. Here we show that these microdomains include Fyn and Lyn kinases. Both kinases are maximally active in myelin prepared from young animals, correlating with early stages of myelination. In the rafts, Fyn kinase is tightly associated with NCAM 120 and F3. In contrast, in oligodendrocyte progenitor cells lacking rafts or in raft-free membrane domains of more mature cells, F3 does not associate with Fyn. The addition of anti-F3 antibodies to oligodendrocytes results in stimulation of Fyn kinase specifically in rafts. Compartmentation of oligodendrocyte GPI-anchored proteins in rafts is thus a prerequisite for association with Fyn, permitting kinase activation. Interaction of oligodendrocyte F3 with axonal ligands such as L1 and ensuing kinase activation may play a crucial role in initiating myelination.  (+info)

Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein. (6/114)

Lipid rafts are regions of the plasma membrane that are enriched in cholesterol, glycosphingolipids and acylated proteins, and which have been proposed as sites for the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Lipid rafts can be isolated on the basis of their insolubility in Triton X-100 at 4 degrees C, with the resulting low-density, detergent-insoluble glycolipid-enriched fraction (DIG) being isolated by flotation through a sucrose density gradient. The detergent-insolubility of APP in mouse cerebral cortex relative to a variety of DIG marker proteins (alkaline phosphatase, flotillin, F3 protein and prion protein) and non-DIG proteins (alkaline phosphodiesterase I, aminopeptidase A and clathrin) has been examined. Alkaline phosphatase, flotillin, F3 protein and the prion protein were present exclusively in the DIG region of the sucrose gradient over a range of protein/detergent ratios used to solubilize the membranes and displayed a characteristic enrichment in the low-density fraction as the protein/detergent ratio was decreased. In contrast, most of the APP, alkaline phosphodiesterase I, aminopeptidase A and clathrin was effectively solubilized at all of the protein/detergent ratios examined. However, a minor proportion of these latter proteins was detected in DIGs at levels which remained constant irrespective of the protein/detergent ratio. When DIGs were isolated from the sucrose gradients and treated with excess Triton X-100, both the DIG marker proteins and APP, alkaline phosphodiesterase I and clathrin were predominantly resistant to detergent extraction at 37 degrees C. These results show that, although a minor proportion of APP is present in DIGs, where it is detergent-insoluble even at 37 degrees C, it behaves as an atypical lipid raft protein and raises questions as to whether lipid rafts are a site for its proteolytic processing.  (+info)

Protein tyrosine phosphatase alpha (PTPalpha) and contactin form a novel neuronal receptor complex linked to the intracellular tyrosine kinase fyn. (7/114)

Glycosyl phosphatidylinositol (GPI)-linked receptors and receptor protein tyrosine phosphatases (RPTPs), both play key roles in nervous system development, although the molecular mechanisms are largely unknown. Despite lacking a transmembrane domain, GPI receptors can recruit intracellular src family tyrosine kinases to receptor complexes. Few ligands for the extracellular regions of RPTPs are known, relegating most to the status of orphan receptors. We demonstrate that PTPalpha, an RPTP that dephosphorylates and activates src family kinases, forms a novel membrane-spanning complex with the neuronal GPI-anchored receptor contactin. PTPalpha and contactin associate in a lateral (cis) complex mediated through the extracellular region of PTPalpha. This complex is stable to isolation from brain lysates or transfected cells through immunoprecipitation and to antibody-induced coclustering of PTPalpha and contactin within cells. This is the first demonstration of a receptor PTP in a cis configuration with another cell surface receptor, suggesting an additional mode for regulation of a PTP. The transmembrane and catalytic nature of PTPalpha indicate that it likely forms the transducing element of the complex, and we postulate that the role of contactin is to assemble a phosphorylation-competent system at the cell surface, conferring a dynamic signal transduction capability to the recognition element.  (+info)

Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression. (8/114)

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.  (+info)

  • We demonstrate that PTPα, an RPTP that dephosphorylates and activates src family kinases, forms a novel membrane-spanning complex with the neuronal GPI-anchored receptor contactin. (rupress.org)
  • This mode of membrane attachment precludes direct transfer of signals into the cell, but allows high mobility in the plane of the membrane, and as such ideally suits contactin for responding to macromolecular stimuli presented to the cell ( Vaughan 1996 ). (rupress.org)
  • The transmembrane and catalytic nature of PTPα indicate that it likely forms the transducing element of the complex, and we postulate that the role of contactin is to assemble a phosphorylation-competent system at the cell surface, conferring a dynamic signal transduction capability to the recognition element. (rupress.org)