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PubMed1990

The product of rab2, a small GTP binding protein, increases neuronal adhesion, and neurite growth in vitro.

The rab genes code for small GTP binding proteins that share with p21ras the ability to bind and hydrolyze GTP. They present significant sequence homologies with the products of YPT1 and SEC4, two small GTP binding proteins involved in the regulation of secretion in the yeast. Several rab genes are expressed in the developing and adult mouse brain. To test directly the possible involvement of these genes in neuronal differentiation, purified rab proteins produced in E. coli were introduced into neurons dissociated from E15 rat midbrain. The most striking effects were obtained with rab2 protein (rab2p). Compared with untreated cells, neurons loaded with rab2p presented an enhanced adhesion to the culture substratum. This phenomenon was visible 3 hr after seeding and was followed within 24 hr by a dramatic increase in neurite growth. Loading the same population of neurons with the products of four other rab genes either decreased neuronal adhesion and neurite growth or had no effect. These experiments suggest that the expression of rab2p plays an important role in neuronal differentiation.

Animals↗
PubMed2002

Rescue of ataxia and preplate splitting by ectopic expression of Reelin in reeler mice.

The gene mutated in reeler (reelin) encodes a protein secreted by neurons in the developing brain that controls laminar positioning of migrating cells in the CNS by an unknown mechanism. To investigate Reelin function, we used the nestin promoter to express Reelin ectopically in the ventricular zone and other brain regions in transgenic mice. In the presence of the endogenous protein, ectopic Reelin did not alter cell migration in the neocortex or the cerebellum. However, in the reeler background, ectopic Reelin induced tyrosine phosphorylation of Dab-1 in the ventricular zone and rescued some, but not all, of the neuroanatomic and behavioral abnormalities characteristic of reeler. These results indicate that Reelin does not function simply as a positional signal. Rather, it appears to participate in multiple events critical for neuronal migration and cell positioning.

Animals↗
PubMed1996

Neuroglian-mediated cell adhesion induces assembly of the membrane skeleton at cell contact sites.

The protein ankyrin links integral membrane proteins to the spectrin-based membrane skeleton. Ankyrin is often concentrated within restricted membrane domains of polarized epithelia and neurons, but the mechanisms responsible for membrane targeting and its segregation within a continuous lipid bilayer remain unexplained. We provide evidence that neuroglian, a cell adhesion molecule related to L1 and neurofascin, can transmit positional information directly to ankyrin and thereby polarize its distribution in Drosophila S2 tissue culture cells. Ankyrin was not normally associated with the plasma membrane of these cells. Upon expression of an inducible neuroglian minigene, however, cells aggregated into large clusters and ankyrin became concentrated at sites of cell-cell contact. Spectrin was also recruited to sites of cell contact in response to neuroglian expression. The accumulation of ankyrin at cell contacts required the presence of the cytoplasmic domain of neuroglian since a glycosyl phosphatidylinositol-linked form of neuroglian failed to recruit ankyrin to sites of cell-cell contact. Double-labeling experiments revealed that, whereas ankyrin was strictly associated with sites of cell-cell contact, neuroglian was more broadly distributed over the cell surface. A direct interaction between neuroglian and ankyrin was demonstrated using yeast two-hybrid analysis. Thus, neuroglian appears to be activated by extracellular adhesion so that ankyrin and the membrane skeleton selectively associate with sites of cell contact and not with other regions of the plasma membrane.

Animals↗
PubMed1991

Neuronal and glial marker proteins in the evaluation of the protective action of MK 801.

A quantitative dot immunobinding procedure was used to quantify glial [the S-100 protein and the glial fibrillary acidic (GFA) protein] and neuronal (the 68- and 200-kDa neurofilament polypeptides, neuron-specific enolase, and neuronal cell adhesion molecule) markers. A single intraperitoneal administration of 10 mg/kg of MK 801 blocked the increase of glial parameters and the decrease in content of neuronal marker proteins that occurred as the response to an N-methyl-D-aspartate (NMDA) lesion in the rat hippocampus. The degradation products of GFA protein and the 68-kDa neurofilament polypeptide that were induced by the NMDA lesion did not appear after MK 801 treatment. This study shows that brain-specific proteins are a set of precise tools for the evaluation of neuroprotective effects of antagonists to excitatory amino acids.

Animals↗
PubMed2003

Ectopic corticospinal tract and corticothalamic tract neurons in the cerebral cortex of yotari and reeler mice.

Reeler and yotari mice, which are mutant for Reelin or Dab1, respectively, show disorders of cerebral cortical lamination. We injected horseradish peroxidase (HRP) into the upper lumbar enlargement to label corticospinal tract (CST) neurons and wheat germ agglutinin-conjugated HRP (WGA-HRP) into the ventral lateral nucleus of the thalamus to label corticothalamic tract (CTT) neurons in both 19-day-old yotari and reeler mice with the aim of discovering whether or not they show differences in the distribution pattern of layer V or layer VI neurons. Similar injections of tracers were made in normal controls. HRP-labeled CST neurons, which were exclusively distributed in layer V of the normal cortex, were radially scattered in the cortex of both mutants, but those in reeler were more deeply distributed than in yotari. WGA-labeled CTT neurons, which were mainly located in layer VI in the normal cortex, were superficially distributed just beneath the pia mater in both reeler and yotari cortex. The present quantitative study shows that the distribution pattern of layer V neurons, but not layer VI neurons, differs between reeler and yotari mice, suggesting that the Reelin and Dab1 proteins may play different roles in the migration and cell positioning of layer V neurons.

Animals↗
PubMed1993

Characterization of NCAM diversity in cultured neurons.

A single transcript of the NCAM gene undergoes differential processing resulting in a multiplicity of mRNAs and their translation products. In this study, the diversity of NCAM in rat primary neuronal cultures was investigated utilizing immuno- and Northern blot analyses. NCAM polypeptides of 190 kDa (NCAM-A) and 135 kDa (NCAM-B) were shown to be associated with the neuronal phenotype. These data were confirmed by Northern blotting, which in both neocortical neurons and cerebellar granule neurons revealed mRNA classes of 7.4 kb and 6.7 kb encoding for NCAM-A and -B, respectively. However, oligonucleotide probes, specific for selected exons or exon combinations, revealed special features of cerebellar granule neurons as compared to neocortical neurons: expression of 4.3 kb NCAM mRNA, a relatively low amount of VASE-containing variants, and an apparent lack of mRNA species containing exons alpha and an AAG insert between exons 12 and 13. Distinct patterns of NCAM mRNA may putatively be related to the regional origin and functional specificity of the investigated neurons.

Alternative Splicing↗
PubMed1996

Structures, alternative splicing, and neurexin binding of multiple neuroligins.

Neuroligin 1 is a neuronal cell surface protein that binds to a subset of neurexins, polymorphic cell surface proteins that are also localized on neurons (Ichtchenko, K., Hata, Y., Nguyen, T., Ullrich, B., Missler, M., Moomaw, C., and Südhof, T. C. (1995) Cell 81, 435-443). We now describe two novel neuroligins called neuroligins 2 and 3 that are similar in structure and sequence to neuroligin 1. All neuroligins contain an N-terminal hydrophobic sequence with the characteristics of a cleaved signal peptide followed by a large esterase homology domain, a highly conserved single transmembrane region, and a short cytoplasmic domain. The three neuroligins are alternatively spliced at the same position and are expressed at high levels only in brain. Binding studies demonstrate that all three neuroligins bind to beta-neurexins both as native brain proteins and as recombinant proteins. Tight binding of the three neuroligins to beta-neurexins is observed only for beta-neurexins lacking an insert in splice site 4. Thus, neuroligins constitute a multigene family of brain-specific proteins with distinct isoforms that may have overlapping functions in mediating recognition processes between neurons.

Alternative Splicing↗
PubMed1989

Expression of N-CAM precedes neural induction in Pleurodeles waltl (urodele, amphibian).

The appearance and localization of N-CAM during neural induction were studied in Pleurodeles waltl embryos and compared with recent contradictory results reported in Xenopus laevis. A monoclonal antibody raised against mouse N-CAM was used. In the nervous system of Pleurodeles, it recognized two glycoproteins of 180 and 140x10(3) M(r) which are the Pleurodeles equivalent of N-CAM-180 and -140. Using this probe for immunohistochemistry and immunocytochemistry, we showed that N-CAM was already expressed in presumptive ectoderm at the early gastrula stage. In late gastrula embryos, a slight increase in staining was observed in the neurectoderm, whereas the labelling persisted in the noninduced ectoderm. When induced ectodermal cells were isolated at the late gastrula stage and cultured in vitro up to 14 days, a faint polarized labelling of cells was observed initially. During differentiation, the staining increased and became progressively restricted to differentiating neurons.

Animals↗
PubMed1995

Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif.

Voltage-gated sodium channels in brain neurons are complexes of a pore-forming alpha subunit with smaller beta 1 and beta 2 subunits. cDNA cloning and sequencing showed that the beta 2 subunit is a 186 residue glycoprotein with an extracellular NH2-terminal domain containing an immunoglobulin-like fold with similarity to the neural cell adhesion molecule (CAM) contactin, a single transmembrane segment, and a small intracellular domain. Coexpression of beta 2 with alpha subunits in Xenopus oocytes increases functional expression, modulates gating, and causes up to a 4-fold increase in the capacitance of the oocyte, which results from an increase in the surface area of the plasma membrane microvilli. beta 2 subunits are unique among the auxiliary subunits of ion channels in combining channel modulation with a CAM motif and the ability to expand the cell membrane surface area. They may be important regulators of sodium channel expression and localization in neurons.

Amino Acid Sequence↗
PubMed1992

Gradient expression of neural cell adhesion molecule (NCAM) in the pontine migratory stream of fetal rats.

Immunohistochemical localization of a neural cell adhesion molecule (NCAM) was examined in the subpial pontine migratory stream of the fetal rat with a monoclonal antibody specific for the rat NCAM, MAb-AF11. Although the pontine cell strand showed weaker expression of NCAM than the parenchymal areas of the brainstem, within the cell strand, NCAM-immunoreactivity was somewhat greater in the anterior part of the stream near the neurons' destination than the caudal part. The weak NCAM gradient in the pontine migratory stream may contribute to formation of the pontine cell strand and the basal pontine gray.

Animals↗
PubMed1991

Development and migration of Purkinje cells in the mouse cerebellar primordium.

The mode of Purkinje cell migration in the mouse cerebellar primordium was examined immunohistochemically, by marking Purkinje cells with anti-spot 35 antibody and labeling them with 5'-bromodeoxyuridine. The cells migrated radially from the neuroepithelium of the fourth ventricle towards the cortical surface between the 13th and 17th days (E13-E17) of gestation. Regional differences in the migratory process were evident: the final settlement of the Purkinje cells proceeded earlier in the lateral and posterior parts of the primordium, exhibiting latero-medial and posteroventral-anterodorsal diminishing sequences. To elucidate the factors involved in the migration, the arrangement of radial glial fibers, and expression of the cell adhesion molecule, tenascin, were examined immunohistochemically with the monoclonal antibody 1D11, a marker for both immature and mature astroglia, and an anti-tenascin antibody. At E14, 1D11-immunopositive fibers were seen to extend from the ventricle to the pial surface, and the cell bodies of immature glia migrated after E15 towards the cortex, shortening the radial processes whose end-feet were attached to the pia mater. Tenascin, which possesses a neuron-glial adhesiveness, was also expressed on the radial fibers during the migration of the Purkinje cells. The fibers were closely apposed to the migratory Purkinje cells, and their arrangement and orientation accorded with the migratory direction of the Purkinje cells. Further, changes in the molecular species of antigens detected by both the 1D11 and anti-tenascin antibodies were observed by immunoblotting analysis during the course of cerebellar development. These findings suggest that the arrangement of radial glia and expression of adhesion molecules may be involved in the control and guidance of Purkinje cell migration.

Animals↗
PubMed1997

Thy-1 and AvGp50 signal transduction complex in the avian nervous system: c-Fyn and G alpha i protein association and activation of signalling pathways.

We have previously reported the isolation of two distinct populations of detergent resistant membrane complexes (DRMC's) from day-old chick brain (Henke et al.: J Neurosci Res 45:617-630, 1996). We now show that the glycosylphosphatidylinositol-anchored proteins Thy-1 and AvGp50 are associated in a signalling complex with c-Fyn, the heterotrimeric G alpha i subfamily members G alpha i-3, G alpha z, and G alpha o, alpha and beta tubulin, and a number of other phosphoproteins in immunocomplexes isolated from both populations of DRMC's. Activation of this signalling complex via Thy-1 monoclonal antibody incubation with chick forebrain cells, elicited a decrease in total phosphoprotein profile and tyrosine kinase activity present in DRMC fractions isolated from these cells, while AvGp50 and control antibodies had no effect. Down-regulation of the DRMC phosphoprotein profile was accompanied by an increase in the Thy-1-associated signalling complex, suggesting that activation of this complex initiates the decreases seen in overall DRMC kinase activity. This signalling complex provides the basis for GPI-anchored protein-mediated signal transduction within the unique plasma membrane domains represented by DRMC's.

Animals↗
PubMed1990

J1/tenascin is a repulsive substrate for central nervous system neurons.

J1/tenascin mediates neuron-astrocyte interactions in vitro and is transiently expressed during CNS development in vivo. It is detectable in discrete zones, for example on astrocytes delineating "barrels" in the rodent somatosensory cortex. To investigate the effects of J1/tenascin on neural cell behavior in vitro, we have generated two monoclonal antibodies specific for protein epitopes on J1/tenascin and used them for immunoaffinity isolation of the molecule from postnatal mouse brain. The purified ECM molecule alone did not support attachment and growth of cerebral astrocytes or E14 mesencephalic, E18 hippocampal, and P6 cerebellar neurons. When various ECM constituents were adsorbed to polyornithine-conditioned glass, a favorable substrate for neural cells, the neurons avoided J1/tenascin-, but not laminin- or fibronectin-coated surfaces, while they grew on J1/tenascin-free, polyornithine-containing areas of the coverslip. In contrast, astrocytes formed uniform monolayers on all of these substrates. We conclude that J1/tenascin could serve to define repulsive territories for CNS neurons from different stages of neural development.

Animals↗
PubMed2002

Robo1 and Robo2 are homophilic binding molecules that promote axonal growth.

In the present study we show that following transfection in 3T3 cells, human Robo1 and Robo2 stimulate neurite outgrowth from Robo-positive neurons (retinal neurons and olfactory neurons), but have no effect on Robo-negative neurons (cerebellar granule cells). The neurite outgrowth response was inhibited by an antibody raised against the first Ig domain of Robo1/2 or by soluble Robo-Fc chimera. Furthermore, we show that the extracellular domains of Robo1 and Robo2 are homophilic adhesion molecules that can also interact with each other. These data suggest a wider range of functions for the Robo family in the development of the nervous system and provide novel insights into the molecular basis for the phenotypes observed in Robo mutants in Drosophila, C. elegans, and zebrafish.

3T3 Cells↗
PubMed2002

Evidence for a cell-specific action of Reelin in the spinal cord.

Reelin, the extracellular matrix protein missing in reeler mice, plays an important role in neuronal migration in the central nervous system. We examined the migratory pathways of phenotypically identified spinal cord neurons to determine whether their positions were altered in reeler mutants. Interneurons and projection neurons containing choline acetyltransferase and/or NADPH diaphorase were studied in E12.5-E17.5 reeler and wild-type embryos, and their final locations were assessed postnatally. While three groups of dorsal horn interneurons migrated and differentiated normally in reeler mice, the migrations of both sympathetic (SPNs) and parasympathetic preganglionic neurons (PPNs) were aberrant in the mutants. Initially reeler and wild-type SPNs were detected laterally near somatic motor neurons, but by E13.5, many reeler SPNs had mismigrated medially. Postnatally, 79% of wild-type SPNs were found laterally, whereas in reeler, 92% of these neurons were positioned medially. At E13.5, both reeler and wild-type PPNs were found laterally, but by E14.5, reeler PPNs were scattered across the intermediate spinal cord while wild-type neurons correctly maintained their lateral location. By postnatal day 16, 97% of PPNs were positioned laterally in wild-type mice; in contrast, only 62% of PPNs were found laterally in mutant mice. In E12.5-E14.5 wild-type mice, Reelin-secreting cells were localized along the dorsal and medial borders of both groups of preganglionic neurons, but did not form a solid barrier. In contrast, Dab1, the intracellular adaptor protein thought to function in Reelin signaling, was expressed in cells having positions consistent with their identification as SPNs and PPNs. In combination, these findings suggest that, in the absence of Reelin, both groups of autonomic motor neurons migrate medially past their normal locations, while somatic motor neurons and cholinergic interneurons in thoracic and sacral segments are positioned normally. These results suggest that Reelin acts in a cell-specific manner on the migration of cholinergic spinal cord neurons.

Animals↗
PubMed1990

Origin and distribution of enteric neurones in Xenopus.

In Xenopus, we investigated the origin of enteric neurones and their distribution in relation to the extracellular matrix (ECM) components, fibronectin (FN) and tenascin (TN). Enteric neurone precursor cells originate from the anterior trunk neural crest (NC). They migrate along the ventromedial NC pathway (between somites and neural tube/notochord) into the primitive gut (via the dorsal mesentery/lateral plate mesoderm) where they differentiate into enteric neurones. NC cells were identified during their migration and in the gut using the X. laevis - X. borealis nuclear marker system. The neuronal character of NC cells in the gut could be demonstrated immunohistochemically with a monoclonal antibody against the HNK-1 epitope. This antibody is superior to N-CAM and neurofilament antibodies which proved insufficient in Xenopus. In early tadpoles (stage 45), enteric neurones occurred frequently in the mesenchymal lining of the oesophagus, either singly or in groups of two to three cells. In more distal portions of the digestive tract, enteric neurones were rarely found. In metamorphosing tadpoles (stage 62/63), enteric neurones were scattered singly beneath the mucosa, or formed small aggregates between the inner and outer muscle layer throughout the length of the digestive tract. The neurones occurred in positions corresponding to the myenteric and submucosal plexus of higher vertebrates. The distribution of enteric neurones was studied in relation to fibronectin (FN) and tenascin (TN), glycoproteins of the ECM, which support (FN) and inhibit (TN) amphibian NC cell migration. Using immunohistochemistry, FN was found during NC cell migration in ECM spaces along the ventromedial pathway, and in the gut between the mucosa and the muscle layers, where it would be able to support adhesion and migration of NC cells. TN, in contrast, appeared much later than FN, both in the dorsal trunk and also ventrally, in the gut. In older tadpoles, TN was present in the mesenchyme and muscle layers of the digestive tract, where it might have an inhibiting influence on the migration of enteric neurones within the gut wall.

Animals↗
PubMed1992

L1 substrate enhances outgrowth of tyrosine hydroxylase-immunoreactive neurites in mesencephalic cell culture.

We have evaluated neurite outgrowth from mesencephalic tyrosine hydroxylase-positive neurons grown in vitro on different substrates. Cultures of ventral mesencephalon from rat embryos (E13) were plated on plastic dishes coated with the following substrates: L1, L2/HNK-1 "residual" (mainly J1/160 but also tenascin), MAG antigens from mouse brains, laminin, fibronectin, poly-L-lysine, RGD peptide, and plastic alone. After 3, 4, and 6 days in vitro, the cultures were stained using an antibody against tyrosine hydroxylase (TH), and the length of TH-positive neurites was measured by computer-assisted image analysis in a double-blind fashion. L1 antigen had a significant positive effect on neurite outgrowth compared to the other substrates studied. Laminin and fibronectin were also favorable substrates. In cultures treated with cytosine arabinoside to prevent mitoses and glial proliferation, the positive effect of L1 was abolished, but laminin still had a stimulatory effect. These data indicate that L1 may be indirectly involved in differentiation or axonal elongation of substantia nigra dopaminergic neurons and suggest a complex effect involving both neurons and glia on dopaminergic neurite development.

Animals↗