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M Schachner

Publications and source records attributed to M Schachner.

At least 145 records · Page 8Linked to original sources
PubMed1997

Neural recognition molecules and synaptic plasticity.

Recent studies of neural recognition molecules have revealed similarities between their functions during ontogenetic development and in neural plasticity in the adult. Observations both at the cellular level in vitro and at the behavioural level in vivo suggest that altered recognition molecule expression can lead to changes in synaptic efficacy, and alterations in synaptic function in turn evoke changes in recognition molecule expression. These changes can manifest themselves as morphological alterations and modulations of the synapse's signal transduction machinery.

Amyloid beta-Protein Precursor↗
PubMed1997

Disruption of the mouse L1 gene leads to malformations of the nervous system.

The adhesion molecule L1 is a member of the immunoglobulin superfamily. L1 is involved in various recognition processes in the CNS and PNS, and binding to L1 can activate signal transduction pathways. Mutations in the human L1 gene are associated with a variable phenotype, including mental retardation and anomalous development of the nervous system, referred to as 'CRASH' (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). We generated an animal model of these conditions by gene targetting. Mutant mice were smaller than wild-type and were less sensitive to touch and pain, and their hind-legs appeared weak and uncoordinated. The size of the corticospinal tract was reduced and, depending on genetic background, the lateral ventricles were often enlarged. Non-myelinating Schwann cells formed processes not associated with axons and showed reduced association with axons. In vitro, neurite outgrowth on an L1 substrate and fasciculation were impaired. The mutant mouse described here will help to elucidate the functions of L1 in the nervous system and how these depend on genetic influences.

Animals↗
PubMed1997

L1/HNK-1 carbohydrate- and beta 1 integrin-dependent neural cell adhesion to laminin-1.

We have shown recently that mouse small cerebellar neurons adhere to a short amino acid sequence of the G2 domain of the laminin alpha 1 chain via the cell surface-expressed HNK-1 carbohydrate. Therefore, we were interested in identifying glycoproteins carrying the HNK-1 carbohydrate at the cell surface of these neurons. Adhesion of small cerebellar neurons to laminin is partially dependent on Ca2+, Mn2+, and Mg2+, indicating the involvement of integrins, which were identified as beta 1, alpha 3, and alpha 6. They could be shown to bind to laminin by a beta 1-dependent adhesion mechanism. None of these subunits was found to carry the HNK-1 carbohydrate. HNK-1-immunoreactive glycoproteins were immunoprecipitated and shown to consist of predominantly one molecular species, which was identified as the neural cell recognition molecule L1. L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin. The binding could be partially inhibited by Fab fragments of monoclonal antibodies against the HNK-1 carbohydrate and against the Ig-like domains of L1. Furthermore, antibodies to the Ig-like domains of L1 and beta 1 integrin inhibited partially cell adhesion to laminin. Determination of the association of L1, beta 1 integrin, and the HNK-1 carbohydrate on the cell surface of live cerebellar neurons by antibody-induced patching and copatching revealed HNK-1 to be linked to L1, but less so to beta 1 integrin. However, only negligible association was found between L1 and beta 1 integrin. Furthermore, it could be shown that adhesion to laminin is mediated by L1/HNK-1- and beta 1 integrin-dependent mechanisms that act at least partially independent of each other.

Animals↗
PubMed1997

Increased intermale aggression and neuroendocrine response in mice deficient for the neural cell adhesion molecule (NCAM).

Mice deficient for the neural cell adhesion molecule (NCAM) show morphological and behavioural abnormalities in the adult form, including a reduced size of the olfactory bulb, reduced exploratory behaviour, and deficits in spatial learning. Here we report increased aggressive behaviour of both homozygous (NCAM -/-) and heterozygous (NCAM +/-) male mutant mice towards an unfamiliar male intruding into their home cage. While plasma testosterone concentrations did not differ between genotypes before or after behavioural testing, corticosterone levels were higher in mutant residents than in wild-type (NCAM +/+) residents 30 min after encountering the intruder. Levels of c-fos mRNA, analysed to monitor neuronal activation, were similar in primary output structures of the olfactory bulb in NCAM-deficient and NCAM +/+ mice, but were increased in brain areas of the limbic system in both NCAM -/- and NCAM +/- mutant mice after the behavioural test. These results indicate that abnormalities in social behaviour correlate with enhanced neuronal activity in limbic brain areas and result in increased social stress in NCAM-deficient mice.

Aggression↗
PubMed1997

Changes in the expression of the extracellular matrix molecules tenascin-C and tenascin-R after 3-acetylpyridine-induced lesion of the olivocerebellar system of the adult rat.

In the central nervous system of rodents, the extracellular matrix glycoproteins tenascin-C and tenascin-R are expressed predominantly by astrocytes and oligodendrocytes respectively. Both molecules support neurite outgrowth from several neuronal cell types when presented as uniform substrates. When offered as a sharp boundary with a permissive substrate, however, both molecules prevent neurite elongation. On the basis of these observations it has been suggested that tenascin-C and tenascin-R may be relevant in determining the cellular response after injury in the adult rodent central nervous system. To investigate whether tenascin-C and tenascin-R may play important functional roles in the lesioned central nervous system, we have analysed their expression in the olivocerebellar system of the adult rat after 3-acetylpyridine-induced degeneration of nerve cells in the inferior olivary nucleus. Tenascin-C mRNA was not detectable at any time in the unlesioned or lesioned inferior olivary nucleus by in situ hybridization. In the cerebellar cortex, tenascin-C mRNA in Golgi epithelial cells was down-regulated 3 days after the lesion and returned to control values 80 days after the lesion. Tenascin-R mRNA was expressed by distinct neural cell types in the unlesioned olivocerebellar system. After a lesion, the density of cells containing tenascin-R transcripts increased significantly in the inferior olivary nucleus and in the white matter of the cerebellar cortex. Immunohistochemical and immunochemical investigations confirmed these observations at the protein level. Our data thus suggest differential functions of tenascin-C and tenascin-R in the injured central nervous system.

Animals↗
PubMed1997

Dying-back oligodendrogliopathy: a late sequel of myelin-associated glycoprotein deficiency.

Ultrastructural analysis of myelin from 8-month-old mice deficient in the myelin-associated glycoprotein revealed pronounced and characteristic alterations of the periaxonal oligodendrocyte processes, consisting of intracytoplasmic deposition of vesicular material, multivesicular bodies, mitochondria, and lipofuscin granules, as well as granular or paracrystalline inclusions. These alterations are similar to those described before as "dying-back oligodendrogliopathy" in diseases of toxic or immune-mediated demyelination including multiple sclerosis.

Animals↗
PubMed1997

Molecular bases of myelin formation as revealed by investigations on mice deficient in glial cell surface molecules.

Several glia-associated cell surface molecules have been implicated in myelin formation in the central (CNS) and peripheral nervous system (PNS). Recent studies in mice deficient for such molecules have been instrumental in understanding the role of these molecules during the formation of the spiraling loops around the axon, compaction of the spiraling loops, determination of the thickness of the myelin sheath, and myelin maintenance. In the PNS, the major peripheral myelin protein PO and the peripheral myelin protein (PMP) 22 are involved in spiral formation as reflected by retarded myelin formation in mice deficient for the respective molecules. An involvement of the myelin-associated glycoprotein (MAG) in this process is detectable only in mice deficient in both PO and MAG, suggesting that PO can replace MAG during the formation of the spiraling loops. Myelin compaction is mediated by both PO and the intracellular myelin component myelin basic protein (MBP). The determination of the correct myelin thickness is mediated by PO, MBP, and PMP22, with PO and MBP fostering and PMP22 attenuating myelin growth. For the maintenance of the association of the Schwann cell and myelin with its ensheathed axon, the myelin components PO, PMP22, MAG, and Connexin 32 are crucial. In the CNS, recognition of oligodendrocytes and axons and the formation of the spiraling loops is mediated by MAG. MAG is additionally responsible for the maintenance of myelin. Myelin compaction is mediated by MBP and by PLP, which fulfills some analogous functions in the CNS as PO in the PNS. These studies reveal that myelin-related cell surface molecules can play distinct but also partially overlapping roles during the formation and maintenance of myelin.

Animals↗
PubMed1996

Microtubule reorganization is obligatory for growth cone turning.

To examine the role of microtubules in growth cone turning, we have compared the microtubule organization in growth cones advancing on uniform laminin substrates with their organization in growth cones turning at a laminin-tenascin border. The majority (82%) of growth cones on laminin had a symmetrical microtubule organization, in which the microtubules entering the growth cone splay out toward the periphery of the growth cone. Growth cones at tenascin borders had symmetrically arranged microtubules in only 34% of cases, whereas in the majority of cases the microtubules were displaced toward one-half of the growth cone, presumably stabilizing in the direction of the turn along the tenascin border. These results suggest that reorganization of microtubules could underlie growth cone turning. Further evidence for the involvement of microtubule rearrangement in growth cone turning was provided by experiments in which growth cones approached tenascin borders in the presence of nanomolar concentrations of the microtubule stabilizing compound, Taxol. Taxol altered the organization of microtubules in growth cones growing on laminin by restricting their distribution to the proximal regions of the growth cone and increasing their bundling. Taxol did not stop growth cone advance on laminin. When growing in the presence of Taxol, growth cones at tenascin borders were not able to turn and grow along the laminin-tenascin border, and consequently stopped at the border. Growth cones were arrested at borders for as long as Taxol was present (up to 6 h) without showing any signs of drug toxicity. These effects of Taxol were reversible. Together, these results suggest that microtubule reorganization in growth cones is a necessary event in growth cone turning.

Actins↗
PubMed1996

Monoclonal antibody O10 defines a conformationally sensitive cell-surface epitope of proteolipid protein (PLP): evidence that PLP misfolding underlies dysmyelination in mutant mice.

Mutations in the gene for proteolipid protein (PLP) have been associated with CNS dysmyelination and abnormal oligodendrocyte death in spontaneous mouse mutants and in Pelizaeus-Merzbacher disease; however, the effect of mutations on PLP structure and function are little understood. We have identified a monoclonal antibody directed against a novel cell surface epitope of PLP, termed O10. By immunofluorescence analysis, COS-7 cells transiently transfected to express PLP (or its isoform DM20) can be stained with antibody O10 and another antibody (A431) directed against the C terminus of PLP/DM20. The subcellular distribution of immunofluorescence labels for the two antibodies is not identical, suggesting that the O10 epitope is acquired post-translationally. When PLP/DM20 from jimpy, jimpymsd, and rumpshaker mutant mice is expressed in COS-7 cells and compared with wild-type PLP/DM20, none of the mutant isoforms displays the O10 epitope, whereas the C-terminal epitope is detected. Because the O10 but not the A431 epitope is also sensitive to SDS and reducing agents, this strongly suggests abnormal protein folding in the PLP mutants. PLP from jimpymsd mice is obviously misfolded, because the amino acid substitution (Ala242 --> Val) is located within a transmembrane domain to which the O10 antibody does not bind. We propose that the O10 epitope emerges as the full length protein reaches a functional tertiary structure and that the absence of this epitope marks a structural defect of PLP that leads to dysmyelination.

Animals↗
PubMed1996

Increased expression of specific recognition molecules by retinal ganglion cells and by optic pathway glia accompanies the successful regeneration of retinal axons in adult zebrafish.

Retinal ganglion cells (RGCs) in adult zebrafish can regenerate their axons. We show that successful axonal regeneration is accompanied by the re-expression by RGCs of mRNAs encoding specific recognition molecules that are expressed at high levels in the larval retina but are down-regulated in the adult. Message levels for 11.1 and 11.2 (two homologs of mammalian L1), n-cam (homologous to mammalian N-CAM), beta 3 (related to the beta 3 and beta 2 subunits of mammalian Na,K-ATPase), and tn-c (homologous to mammalian tenascin-C) were high in larval RGCs undergoing axonogenesis and low in adult RGCs. After an optic nerve crush, axotomized adult RGCs showed increased levels of 11.1, 11.2 and n-cam mRNA expression, whereas the levels of beta 3 and tn-cmRNA remained unchanged. The optic nerve crush also induced the expression of some of these mRNAs in the optic nerve and tract where they are not normally detectable. This lesion induced up-regulation by presumptive glia was observed for 11.1, 11.2, n-cam and beta 3 but not for tn-c. The combination of a neuronal (intrinsic) response to axotomy with an environmental (extrinsic) response may be an important determinant allowing for the successful axonal regeneration.

Animals↗
PubMed1996

Expression of a Na,K-ATPase beta 3 subunit during development of the zebrafish central nervous system.

Zebrafish beta 3, a full length cDNA clone encoding a zebrafish Na,K-ATPase beta subunit, was isolated. The protein shares highest homology with the beta 3 subunits of amphibians and mammals, slightly less homology with the beta 2 subunits, and is distinct from the beta 1 subunits. The fish beta subunit co-assembled with alpha subunits to form Na,K-ATPase enzymes when expressed in Xenopus oocytes. Embryonic expression was first detected by whole-mount in situ hybridization between 8-12 hr post-fertilization (hpf) in the head mesoderm. Subsequently, and up to 24 hpf, the mRNA was confined to four dorsal domains in the anterior neural tube. After a transient downregulation during the second day, expression was again conspicuous in the nervous system of 3-day-old larvae. Based on its distribution pattern, the fish beta subunit could be involved in setting up regional identities in the developing fish CNS and in the differentiation of distinct cell types.

Amino Acid Sequence↗
PubMed1996

In vitro oligodendrogliotrophic properties of cell adhesion molecules in the immunoglobulin superfamily: myelin-associated glycoprotein and N-CAM.

To determine if cell recognition molecules interact trophically with oligodendrocytes (OCs), their effect as growth substrates for differentiating oligodendroblasts was studied in primary culture. Oligodendroblasts purified from postnatal rat cerebrum by immunopanning were plated on substratum-bound cell adhesion molecules or extracellular matrix glycoproteins in chemically defined medium in which OCs terminally differentiate but survive poorly. Growth on myelin-associated glycoprotein (MAG) and neural cell adhesion molecule (N-CAM) selectively increased the number of viable cells per culture 2 weeks after plating as much as tenfold and sixfold, respectively, over background survival on an albumin substrate, whereas L1, tenascin-R, tenascin-C, fibronectin, and laminin were ineffective. Neither MAG nor N-CAM stimulated bromodeoxyuridine incorporation into cultures, indicating that enhanced proliferation did not contribute to better survival. Compared to growth on polyornithine alone, oligodendroblast differentiation in the added presence of MAG or N-CAM was qualitatively unchanged; > 90% of surviving cells developed into OCs that matured further by immunocytochemical and morphological criteria. A striking difference, however, was the quantitative effect of MAG and N-CAM substrates on oligodendrite outgrowth, increasing myelin-like membrane formation two- to threefold (> 8 x 10(3) microns2/cell). These findings support the concept that autotypic or heterotypic cell contact-mediated signaling by recognition molecules at the OC surface contributes trophic support of myelinogenesis.

Animals↗
PubMed1996

Testosterone elevates expression of tenascin-R and oligomannosidic carbohydrates in developing male zebra finches.

The song system of zebra finches is a model for studying the influence of steroids on neural connectivity and behavior during development. To investigate the molecular mechanisms underlying the song-related and gonadal hormone-regulated development of neural activity, we have chosen to investigate the expression of recognition molecules in the brain nuclei associated with motor control of song production. Here we show that testosterone accelerates expression of the predominantly oligodendroglia-, but also neuron-associated extracellular matrix glycoprotein tenascin-R and the oligomannosidic carbohydrate L3 during the third and seventh posthatching week in the higher vocal center (HVC) and robust nucleus of the archistriatum (RA), but not in other brain regions. The results suggest that recognition molecules and associated carbohydrate structures can be regulated by testosterone and that an increased expression of these molecules correlates with testosterone-induced modifications of song behavior.

Animals↗
PubMed1996

Reduction of hippocampal long-term potentiation in transgenic mice ectopically expressing the neural cell adhesion molecule L1 in astrocytes.

The influence of the neural cell adhesion molecule L1 on hippocampal long-term potentiation (LTP) was investigated using transgenic mice ectopically expressing L1 in astrocytes (GFAP-L1). L1 is a member of the immunoglobulin superfamily of homophilic adhesion molecules predominantly expressed in neurones. Previously, it has been demonstrated that local application of L1 antibodies and recombinant L1 fragments impair the expression of LTP. Here, we show that LTP induced by theta-burst stimulation or by pairing presynaptic stimulation with postsynaptic depolarisation was strongly reduced in GFAP-L1 mice, whereas basal synaptic transmission, post-tetanic potentiation, and paired-pulse facilitation were not modified. These results further support the idea that L1 is involved in synaptic plasticity and suggest that adhesion molecule-dependent changes in synaptic morphology contribute to the expression of LTP.

Animals↗
PubMed1996

Structure of the HNK-1 carbohydrate epitope on bovine peripheral myelin glycoprotein P0.

The HNK-1 carbohydrate epitope, expressed by many neural recognition molecules, is involved in cell interactions that control cell type-specific neurite outgrowth and regeneration. It is also the target for autoimmune IgM antibodies in demyelinating neuropathies of the peripheral nervous system in humans. Despite its acknowledged importance in cell interactions, the HNK-1 carbohydrate structure, when expressed on glycoproteins, is still unknown. Here, we describe the structure of one of the predominant HNK-1-bearing glycans of bovine P0. The epitope consists of the sulfated trisaccharide SO4-3GlcAbeta1-3Galbeta1-4GlcNAc, attached to the alpha1-6 arm of a diantennary core with a bisecting N-acetylglucosamine. It is the first example of a terminal 3-sulfated glucuronic acid on an asparagine-linked carbohydrate. Because the similarity between the glycoprotein-derived structure and the glycosphingolipids carrying HNK-1 is restricted to the terminal sulfated trisaccharide, we conclude that this element is sufficient for HNK-1 immunoreactivity. Knowledge of the HNK-1 structure on proteins is an important prerequisite for the elucidation of its functional role in development and disease.

Animals↗
PubMed1996

The clustering of axonal sodium channels during development of the peripheral nervous system.

The distribution of Na+ channels in rat peripheral nerve was measured during development by using immunofluorescence. Small segments of sciatic nerve from postnatal day 0-13 (P0-P13) pups were labeled with an antibody raised against a well conserved region of the vertebrate Na+ channel. At day P0 axons contained almost no Na+ channel aggregates. The number of clusters increased dramatically throughout the first week. In almost all cases Na+ channels clustered in the vicinity of Schwann cell processes. At least four classes of aggregates were noted. Clusters formed singly at Schwann cell edges, in pairs or in broad regions between neighboring Schwann cells, and in more focal zones at presumptive nodes. Almost all Na+ channel aggregates had reached the latter stage by the end of the first week. Histograms plotting the frequency of occurrence of each cluster type suggested a sequence of events in node formation involving the initiation of channel aggregation by Schwann cell processes. The requirement for Schwann cells during sodium channel clustering was tested by blocking proliferation of these cells with the antimitotic agent mitomycin C. Na+ channel clustering was sharply reduced, whereas node formation was normal at a distal site along the same nerve. Immunocytochemical detection of myelin-associated glycoprotein (MAG) indicated that Schwann cells must begin to ensheathe axons before inducing Na+ channel clustering.

Aging↗
PubMed1996

The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation.

The alpha-2,8-linked polysialic acid (PSA) modification of the neural cell adhesion molecule (NCAM) modulates morphogenetic cell interactions. PSA is strongly expressed during neural development and generally down-regulated in the adult. However, it remains prominent in some areas of the brain, e.g., the hippocampus. We assayed the functional role(s) of PSA in synaptic plasticity in the hippocampus in two experimental paradigms by removing PSA with endo-neuraminidase NE (endo-N) an enzyme which specifically cleaves alpha-2,8-linked polysialic acid. (1) The acquisition and retention of spatial memory of rats in the Morris water maze, critically dependent on the hippocampus, was significantly impaired after a localized injection of endo-N into the hippocampus, whereas visual and motor capacities were unaffected. (2) Tetanic stimulation of the Schaffer collaterals in endo-N-treated hippocampal slices in vitro failed to elicit LTP and yielded only a short post-tetanic potentiation, but the response returned to control levels within 2 minutes, whereas basal synaptic activity and short-term potentiation were not affected. Our findings suggest that the carbohydrate epitope PSA plays an important role in synaptic plasticity.

Analysis of Variance↗