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At least 271 records · Page 15Linked to original sources
PubMed2000

Impaired axonal regeneration in alpha7 integrin-deficient mice.

The interplay between growing axons and the extracellular substrate is pivotal for directing axonal outgrowth during development and regeneration. Here we show an important role for the neuronal cell adhesion molecule alpha7beta1 integrin during peripheral nerve regeneration. Axotomy led to a strong increase of this integrin on regenerating motor and sensory neurons, but not on the normally nonregenerating CNS neurons. alpha7 and beta1 subunits were present on the axons and their growth cones in the regenerating facial nerve. Transgenic deletion of the alpha7 subunit caused a significant reduction of axonal elongation. The associated delay in the reinnervation of the whiskerpad, a peripheral target of the facial motor neurons, points to an important role for this integrin in the successful execution of axonal regeneration.

Animals↗
PubMed1993

Functional characterization of beta isoforms of murine Na,K-ATPase. The adhesion molecule on glia (AMOG/beta 2), but not beta 1, promotes neurite outgrowth.

We have previously provided evidence for a dual function of the adhesion molecule on glia (AMOG/beta 2), the beta 2 subunit of the murine Na,K-ATPase, both as neural recognition molecule mediating neuron-glia interactions and as functional beta subunit of the sodium pump. To analyze the functional role of AMOG/beta 2 in neurite outgrowth, AMOG/beta 2-expressing L-cells were generated by transfection and used as substrates for neurite outgrowth of cerebellar and hippocampal neurons. AMOG/beta 2-transfected L-cells led to an increase in neurite length after 6 h, which was specifically inhibited by antibodies to AMOG/beta 2 and a neuronal membrane fraction. Moreover, the extracellular domain of AMOG/beta 2 generated as a soluble recombinant protein in Chinese hamster ovary cells partially inhibited the increase in neurite outgrowth on AMOG/beta 2-transfected L-cells. L-cells transfected with the mouse beta 1 subunit had no effect on neurite extension. Our observations show for the first time differences in functional properties for different beta isoforms of the Na,K-ATPase and suggest that AMOG/beta 2 but not beta 1 is able to interact with an unknown neuronal receptor leading to increased neurite outgrowth, most likely via signal transduction.

Adenosine Triphosphatases↗
PubMed1995

Reelin: a novel extracellular matrix protein involved in brain lamination.

Normal development of the nervous system is achieved through an elaborate program of guided neuronal migration and axonal growth. In the last few years, a flood of research has dissected the molecular bases of these phenomena, and several cell-surface and extracellular matrix molecules, which are implicated in neuronal and axonal targeting processes, have been recognized. Taking this knowledge a step further, a recent paper by Tom Curran's group reports the molecular cloning of the gene deleted in the autosomal recessive mouse mutation reeler, affecting cortical neuronal migration. This gene encodes reelin, a novel extracellular matrix protein.

Animals↗
PubMed2002

Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression.

Mutations in the L1CAM gene cause a highly variable neurological disease described as X-linked hydrocephalus, MASA syndrome or spastic paraplegia type I. Over one-third of the mutations identified in affected boys are missense, unique to individual families and distributed primarily across the large extracellular domain of the L1 protein. We have examined the effects of 25 missense mutations on binding to homophilic (L1) and heterophilic (TAX-1) ligands as well as on intracellular trafficking. All but three of these result in reduced ligand binding or impaired movement to the surface of COS and CHO cells. Therefore, we demonstrate for the first time that most missense mutations found in affected families have functional consequences. Furthermore, mutations that are predicted to affect the structure of individual extracellular domains are more likely to affect intracellular processing and/or ligand binding than those mutations affecting surface properties of the molecule.

Animals↗
PubMed2000

Derangement of Purkinje cells in the rat cerebellum following prenatal exposure to X-irradiation: decreased Reelin level is a possible cause.

It has been reported that prenatal X-irradiation of rats during the late gestation period causes heterotopic Purkinje cells in the internal granular layer (IGL) of the abnormally foliated cerebellum. The present study was designed to demonstrate the process of X-ray-induced derangement of Purkinje cells and their surrounding cells. In addition, the expression of some morphoregulatory molecules was examined to determine which molecules are involved in the abnormal pattern of Purkinje cells. Pregnant rats (n = 22) were exposed to 2.5 Gy X-radiation on gestation day 21 and the cerebellum of progeny was examined histologically and by immunohistochemistry to identify Purkinje and Bergmann cells. At 12 h after exposure, extensive cell death was observed in the external granular layer (EGL). By postnatal day (P) 9, while Purkinje cells with well-developed dendrites aligned underneath the EGL in the control cerebellum, Purkinje cells with shorter and abnormally oriented dendrites failed to align and remained in the heterotopic location in the IGL. Bergmann cells and their fibers were also disoriented but later recovered in their proper position. Abnormal folia developed in the irradiated rats. Using immunohistochemistry, we next examined the levels of the neural cell adhesion molecule (NCAM), fibronectin, tenascin, and Reelin. Among them, only the level of Reelin was affected significantly. Reelin decreased strikingly in the premigratory zone of the EGL and IGL in the irradiated cerebellum on P1, and the decrease continued until P9. Decreased Reelin expression was demonstrated quantitatively by Northern blot analysis and the correlation between the mRNA and protein levels was well presented. The expression of reelin mRNA decreased significantly by irradiation from P0, being almost one third of the level in controls on P4, and tended to recover up to P9. It is thus indicated that X-irradiation causes a marked decrease in the level of Reelin at the critical stage for the alignment of Purkinje cells. Since Reelin has been shown to play an important role in the migration of neural cells, it is suggested that the decrease in Reelin by X-irradiation is an important factor for the derangement of Purkinje cells.

Animals↗
PubMed1995

Localization of NCAM on NCAM-B-expressing cells with inhibited migration in collagen.

The extracellular matrix is a key element in neuronal development and tumour invasion, providing a substratum which sustains the adhesion and migration of cells. In order to study interactions between the neural cell adhesion molecule (NCAM) and collagen, we transfected mouse L cells with cDNA encoding the human transmembrane NCAM isoform of 140 kDa (NCAM-B). An L-cell/collagen type I system was used to study the influence of NCAM expression on in vitro invasion. We here report that migration of NCAM-expressing cells in collagen was inhibited compared to that of NCAM-negative cells transfected with the empty vector. Immunofluorescence confocal laser scanning microscopy (CLSM) and immunogold electron microscopy using anti-human NCAM antibodies demonstrated a heterogeneous distribution of NCAM on the plasma membrane of transfected L cells grown on collagen. NCAM was preferentially located at the surface of broad cytoplasmic protrusions and slender extensions, some of which were facing the collagen. This was in contrast to the homogeneous surface distribution of NCAM on cells grown on plastic. These data suggest that NCAM and collagen type I interact, and that this might lead to the migration inhibition of NCAM-expressing cells.

Animals↗
PubMed1993

Degradation fragments of L1 antigen enhance tyrosine hydroxylase-immunoreactive neurite outgrowth in mesencephalic cell culture.

The L1 antigen has been implicated in adhesion events controlling axonal elongation during formation of major fiber tracts, and promotes neurite outgrowth in culture. It is possible that injury of brain tissue causes neuronal surface molecules such as L1 antigen to be shed, and degradation fragments may therefore be present adjacent to the damage. These L1 fragments might then influence regeneration or injury-induced growth. We have evaluated neurite outgrowth from tyrosine hydroxylase-positive (TH +) E13 mesencephalic neurons grown in vitro on a substrate of mouse L1 antigen and on L1 degradation fragments separated by molecular weight. Mouse myelin-associated glycoprotein (MAG), laminin, poly-D-lysine, and fetal calf serum served as control substrates. L1 antibodies were added to one set of cultures (experimental), and compared to control cultures containing normal rabbit serum. After 3 days in vitro, the cultures were stained using an antibody against TH, and the length of the TH + neurites was measured by computer-assisted image analysis in a double-blind fashion. TH+ neurites were significantly longer when grown on L1 antigen, as well as on L1 degradation fragments, as compared to the control substrates. As compared to control normal rabbit serum, L1 antibodies eliminated the neurite-promoting effect of both the L1 substrate and the L1 degradation products. In addition, L1 substrates promoted clustering of TH + cells and the formation of loose bundles of TH + neurites. It is suggested that the L1 substrates influence TH-immunoreactive neurite outgrowth, at least partially, through indirect effects on glial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Alginate immobilized mammalian neurons: a potential tool to isolate new neuronal ligands.

We developed improved immobilization conditions which permitted (i) to immobilize neuroblastoma cells (N18) in calcium-alginate gel beads, (ii) to test the function of ionic channels using patch-clamp electrophysiological techniques and (iii) to quantitatively analyze ligand interactions with voltage-dependent sodium channels in neurons inside the beads. These results qualify this immobilization technique for the isolation and/or purification of ligands specific for neuronal cells.

Alginates↗
PubMed1996

Characterization of developmental stage and neuronal potential of the rat PNS-derived stem cell line, RT4-AC.

RT4 is a family of cell lines derived from a rat peripheral neurotumor and consists of a multipotential stem cell line that spontaneously gives rise to three derivative cell types: one glial-like and two neuronal-like. Previous studies have established that the RT4 glial derivative expresses many properties of Schwann cells; however, the neuronal designation of the other RT4 derivatives is less well substantiated. To further characterize the developmental stage and lineages represented by the RT4 stem cell and its derivatives we examined the expression of 16 marker genes whose expression is either specific to neurons or in some cases, neural tissue. Taken together our results indicate that (i) the RT4 neuronal-like derivatives express only immature neuronal properties, (ii) the RT4 cell lines most closely resemble neural crest derivatives from embryonic day 10 to 12 in the rat, (iii) treatment with cAMP and steroids, although capable of promoting process extension by the RT4 neuronal-like derivatives, did not affect the expression of any of the 16 marker genes examined, and (iv) when compared to other neural stem cell systems, RT4-AC generates the most immature neuronal derivatives.

Animals↗
PubMed1997

Neuronal position in the developing brain is regulated by mouse disabled-1.

During mammalian brain development, immature neurons migrate radially from the neuroectoderm to defined locations, giving rise to characteristic cell layers. Here we show that targeted disruption of the mouse disabled1 (mdab1) gene disturbs neuronal layering in the cerebral cortex, hippocampus and cerebellum. The gene encodes a cytoplasmic protein, mDab1 p80, which is expressed and tyrosine-phosphorylated in the developing nervous system. It is likely to be an adaptor protein, docking to others through its phosphotyrosine residues and protein-interacting domain. The mdab1 mutant phenotype is very similar to that of the reeler mouse. The product of the reeler gene, Reelin, is a secreted protein that has been proposed to act as an extracellular signpost for migrating neurons. Because mDab1 is expressed in wild-type cortical neurons, and Reelin expression is normal in mdab1 mutants, mDab1 may be part of a Reelin-regulated or parallel pathway that controls the final positioning of neurons.

Animals↗
PubMed2004

Radial and tangential neuronal migration disorder in ibotenate-induced cortical lesions in hamsters: immunohistochemical study of reelin, vimentin, and calretinin.

To investigate the mechanisms of radial and tangential neuronal migration disorders, immunohistochemical expressions of reelin, vimentin, and calretinin were examined in brain lesions induced by ibotenate (an agonist of the N-methyl-D-aspartate [NMDA] complex receptor) in hamsters. Thirty-four newborn hamsters were subjected to intracerebral injections of ibotenate, and 12 animals served as the control. These hamsters were examined at 1, 2, 3, 5, and 7 days after injections. The cortical lesions observed after ibotenate injections had a strong resemblance to the following neuronal migration disorders: (1) microgyria, (2) focal subcortical heterotopia, and (3) leptomeningeal glioneuronal heterotopia. In microgyria, the radial glial fibers were sparsely distributed, but in leptomeningeal glioneuronal heterotopia, vimentin-positive fibers extended into this abnormal neural tissue. Calretinin-immunoreactive neurons and fibers were present along the lesion forming the microgyria and abnormal neuronal arrangement. Focal subcortical heterotopia also included a small number of calretinin-expressing neurons originating from the subplate neuronal population. These results imply that the neuronal migration disorders produced by ibotenate show not only the migrational arrest of neurons but also interference from the termination of the migration process. We also suggest that the heterotopic neurons constituting the focal subcortical heterotopia originate in the lateral or medial ganglionic eminence of the ventral telencephalon, probably caused by the abnormal tangential neuronal migration.

Animals↗
PubMed1991

NCAM polysialic acid can regulate both cell-cell and cell-substrate interactions.

We have proposed previously that the polysialic acid (PSA) moiety of NCAM can influence membrane-membrane apposition, and thereby serve as a selective regulator of a variety of contact-dependent cell interactions. In this study, cell and tissue culture models are used to obtain direct evidence that the presence of PSA on the surface membrane can affect both cell-cell and cell-substrate interactions. Using a neuroblastoma/sensory neuron cell hybrid, it was found that removal of PSA with a specific neuraminidase (endo-N) augments cell-cell aggregation mediated by the L1 cell adhesion molecule as well as cell attachment to a variety of tissue culture substrates. In studies of embryonic spinal cord axon bundling, which involves both cell-cell and cell-substrate interactions, the pronounced defasciculation produced by removal of PSA is most easily explained by an increase in cell-substrate interaction. The fact that in both studies NCAM's intrinsic adhesion function was found not to be an important variable further illustrates that regulation of the cell surface by PSA can extend beyond binding mediated by the NCAM polypeptide.

Animals↗
PubMed1994

Activity-dependent mobilization of the adhesion molecule polysialic NCAM to the cell surface of neurons and endocrine cells.

The alpha-2,8-linked sialic acid polymer (PSA) on the neural cell adhesion molecule (NCAM) is an important regulator of cell surface interactions. We have examined the translocation of PSA-NCAM to the surface of cultured cortical neurons and insulin secreting beta cells under different conditions of cell activity. Endoneuraminidase N, an enzyme that specifically cleaves PSA chains, was used to remove pre-existing PSA from the plasma membrane and the re-expression of the molecule was monitored by immunocytochemistry. Punctate PSA immunostaining was restored on the surface of 68% of neurons within 1 h. This recovery was almost completely prevented by tetrodotoxin, suggesting that spontaneous electrical activity is required. K+ depolarization (50 mM) allowed recovery of PSA surface staining in the presence of tetrodotoxin and this effect required the presence of extracellular Ca2+. Rapid redistribution of PSA-NCAM to the surface of beta cells was observed under conditions that stimulate insulin secretion. Ca2+ channel inhibition decreased both PSA-NCAM expression and insulin secretion to control, non-stimulated levels. Finally, subcellular fractionation of an insulin-secreting cell line showed that the secretory vesicle fraction is highly enriched in PSA-NCAM. These results suggest that PSA-NCAM can be translocated to the cell surface via regulated exocytosis. Taken together, our results provide unprecedented evidence linking cell activity and PSA-NCAM expression, and suggest a mechanism for rapid modulation of cell surface interactions.

Animals↗
PubMed2006

The extracellular matrix provides directional cues for neuronal migration during cerebellar development.

Normal central nervous system development relies on accurate intrinsic cellular programs as well as on extrinsic informative cues provided by extracellular molecules. Migration of neuronal progenitors from defined proliferative zones to their final location is a key event during embryonic and postnatal development. Extracellular matrix components play important roles in these processes, and interactions between neurons and extracellular matrix are fundamental for the normal development of the central nervous system. Guidance cues are provided by extracellular factors that orient neuronal migration. During cerebellar development, the extracellular matrix molecules laminin and fibronectin give support to neuronal precursor migration, while other molecules such as reelin, tenascin, and netrin orient their migration. Reelin and tenascin are extracellular matrix components that attract or repel neuronal precursors and axons during development through interaction with membrane receptors, and netrin associates with laminin and heparan sulfate proteoglycans, and binds to the extracellular matrix receptor integrins present on the neuronal surface. Altogether, the dynamic changes in the composition and distribution of extracellular matrix components provide external cues that direct neurons leaving their birthplaces to reach their correct final location. Understanding the molecular mechanisms that orient neurons to reach precisely their final location during development is fundamental to understand how neuronal misplacement leads to neurological diseases and eventually to find ways to treat them.

Cell Adhesion Molecules, Neuronal↗
PubMed1995

The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons.

In the neurological mutant mouse reeler, the histological organization of the neocortex develops abnormally and essentially results in an inversion of the relative positions of the cortical layers. The reeler mutation, therefore, provides an insight into the molecular mechanisms underlying the formation of the cortical layers. We have generated a monoclonal antibody (CR-50) that probes a distinct allelic antigen present in wild-type but not in reeler mutant mice. CR-50 reacted specifically with Cajal-Retzius neurons, one of the first cortical neurons to differentiate in the neocortex, but whose functional role is not known. When dissociated cerebral cortical cells were incubated with CR-50 in reaggregation culture, the genotype-dependent histogenetic assembly of wild-type cortical cells resembled that of reeler mutants. These findings revealed that the selective expression of a distinct molecule on Cajal-Retzius neurons is critical for the normal lamination of cortical neurons in the mammalian neocortex.

Animals↗
PubMed2001

Mobilization of the cell adhesion glycoprotein F3/contactin to axonal surfaces is activity dependent.

F3/contactin is a cell adhesion/recognition molecule of the immunoglobulin superfamily implicated in axonal growth. We examined its subcellular distribution and mobilization to the cell surface in oxytocin- (OT-) secreting neurons, which express it throughout life and the axons of which undergo activity-dependent remodelling. This was performed in hypothalamic organotypic slice cultures containing OT neurons with properties of adult neurosecretory cells. Immunocytochemistry and immunoblot analysis confirmed that OT neurons express high levels of F3/contactin in vitro. Light and confocal microscopy of cultures that underwent double immunofluorescence after fixation showed F3/contactin immunoreactivity throughout the cytoplasm of OT somata, dendrites and axons, and also in non-OT axons and in putative synaptic boutons which contacted OT neurons. By contrast, after treatment of live cultures with anti-F3/contactin antibodies followed by double immunofluorescence for the glycoprotein and OT, F3/contactin immunoreactivity was visible only on the surface of axons, whether or not OT-immunoreactivity was present. Because of its glycosylphosphatidyl-inositol (GPI) linkage, F3/contactin can occur in a membrane-bound or soluble form. As seen from immunocytochemistry of live cells and immunoblot analysis, treatment of cultures with a GPI-specific phospholipase C (GPI-PLC) resulted in loss of F3/contactin immunoreactivity from all cell surfaces. F3/contactin immunoreactivity reappeared on axonal surfaces within 5 h after enzyme washout. Such re-expression was accelerated by neuronal activity facilitation (by K+ depolarization or gamma-aminobutyric acid (GABA)-A receptor blockade with bicuculline) and inhibited by neuronal activity repression [by blockade of Ca2+ channels with Mn2+, Na+ channels with tetrodotoxin (TTX) or excitatory inputs with glutamate antagonists]. Our observations establish therefore that F3/contactin surface expression in hypothalamic neurons is polarized to the axons where it occurs mainly in a GPI-linked form. We also provide direct evidence that externalization of F3/contactin depends on Ca2+ entry and neuronal electrical activity. Taken together with our earlier finding that the glycoprotein is localized in neurosecretory granules, we demonstrate that F3/contactin is mobilized to the axonal surface via the activity-dependent regulated pathway, thus arriving at the correct place and time to intervene in activity-dependent remodelling of axons.

Action Potentials↗
PubMed2001

The contactin-related protein FAR-2 defines purkinje cell clusters and labels subpopulations of climbing fibers in the developing cerebellum.

FAR-2 is a novel neural member of the Ig superfamily, which is related to F11/F3/contactin and axonin-1/TAG-1. This protein is expressed by subpopulations of Purkinje cells in the chicken cerebellum and FAR-2-positive clusters of these neurons alternate with FAR-2-negative clusters in both tangential dimensions of the cerebellar cortex. Furthermore, FAR-2 is also expressed by one type of Purkinje cell afferents, namely, the climbing fibers, and different subpopulations of these axons show distinct levels of FAR-2 expression. Homology modeling using axonin-1 as a template reveals that the four aminoterminal Ig domains of FAR-2 form a compact U-shaped structure, which is likely to contain functionally important ligand-binding sites. FAR-2 is binding to the Ig superfamily protein NgCAM/L1, but not to the related receptor NrCAM, and it is also interacting with the modular ECM protein tenascin-R. These results suggest that FAR-2 may contribute to the formation of somatotopic maps of cerebellar afferents during the development of the nervous system.

Amino Acid Sequence↗