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PubMed1982

Chemical characterization of a neural cell adhesion molecule purified from embryonic brain membranes.

A neural cell adhesion molecule (N-CAM) was purified in milligram quantities from detergent extracts of embryonic chick brain membranes. N-CAM has an unusual carbohydrate content and structure, is polydisperse in solution, and is associated with proteolytic activity leading to its spontaneous cleavage. The carbohydrate composition of N-CAM includes 13 mol of sialic acid but only 1.4 mol of galactose/100 mol of amino acids, suggesting the presence of a sialic acid to protein linkage not previously observed in higher organisms. N-CAM appears to be an integral membrane protein in that its extraction from membranes required detergent. Although soluble, the purified molecule was aggregated (Mr = 0.5 to 1.2 X 10(6)) and polydisperse in detergent-free solutions. N-CAM from brain also migrated as a broad but continuously stained region from Mr = 200,000 to Mr = 250,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis; the molecule from retina was similar but had a somewhat faster mobility. Desialation of N-CAM did not significantly change its behavior in solution, but converted both brain and retinal N-CAM to components migrating on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as material of about Mr = 140,000. Despite the apparent heterogeneity, amino acid sequence analysis and comparison of proteolytic fragments suggest that all forms of the glycoprotein are derived from the same polypeptide chain. On prolonged incubation at neutral pH, N-CAM undergoes apparent proteolysis to yield a polypeptide that contains little sialic acid and has a Mr = 65,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a separate sialic acid-rich component, and a variety of small peptides. The 65,000-dalton polypeptide appeared to contain all of the antigenic determinants of intact N-CAM that neutralize the adhesion-blocking ability of anti-retinal cell Fab' fragments.

Amino Acid Sequence↗
PubMed2000

Neurite outgrowth induced by a synthetic peptide ligand of neural cell adhesion molecule requires fibroblast growth factor receptor activation.

The neural cell adhesion molecule NCAM is involved in axonal outgrowth and target recognition in the developing nervous system. In vitro, NCAM-NCAM binding has been shown to induce neurite outgrowth, presumably through an activation of fibroblast growth factor receptors (FGFRs). We have recently identified a neuritogenic ligand, termed the C3 peptide, of the first immunoglobulin (lg) module of NCAM using a combinatorial library of synthetic peptides. Here we investigate whether stimulation of neurite outgrowth by this synthetic ligand of NCAM involves FGFRs. In primary cultures of cerebellar neurons from wild-type mice, the C3 peptide stimulated neurite outgrowth. This response was virtually absent in cultures of cerebellar neurons from transgenic mice expressing a dominant-negative form of the FGFR1. Likewise, in PC12E2 cells transiently expressing a dominant-negative form of the mouse FGFR1, induction of neurites by the C3 peptide was abrogated. These findings suggest that the neuritogenic effect of the C3 peptide requires the presence of functional FGFRs and support the hypothesis that FGFRs are essential in cell adhesion molecule-stimulated neurite outgrowth. The C3 peptide appears to stimulate neurite outgrowth by specifically activating an NCAM-FGFR-dependent signaling cascade and may therefore be of considerable interest as a tool for the determination of NCAM-dependent neurite outgrowth as well as a potential drug capable of promoting outgrowth and regeneration of NCAM-responsive axons.

3T3 Cells↗
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↗
PubMed2001

Characterization of N-glycans from mouse brain neural cell adhesion molecule.

The N-glycosylation pattern of the neural cell adhesion molecule (NCAM), isolated from brains of newborn mice, has been analyzed. Following digestion with trypsin, generated glycopeptides were fractionated by serial immunoaffinity chromatography using immobilized monoclonal antibodies specifically recognizing polysialic acid (PSA) units or the HNK1-carbohydrate epitope. Subsequent analyses of the resulting (glyco)peptides by Edman degradation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) revealed polysialylated glycans to be exclusively linked to glycosylation sites 5 (Asn(431)) and 6 (Asn(460)), whereas glycans carrying the HNK1-epitope could be assigned to sites 2 (Asn(297)), 5, 6, and, to a lesser extent, site 3 (Asn(329)). PSA-, HNK1-, and non-PSA/HNK1-glycan fractions were characterized by carbohydrate constituent and methylation analyses as well as MALDI-TOF-MS in conjunction with chromatographic fractionation techniques. The results revealed that the core structures of PSA-glycans represented predominantly fucosylated, partially sulfated 2,6-branched isomers of triantennary as well as tetraantennary complex-type glycans, whereas carbohydrate chains bearing the HNK1-epitope were dominated by diantennary species carrying in part bisecting GlcNAc residues. Non-PSA/HNK1-glycans exhibited a highly heterogeneous pattern of partially truncated, mostly diantennary structures being characterized by the presence of additional fucose, bisecting GlcNAc and/or sulfate residues. In conclusion, our results revealed that the glycosylation pattern of murine NCAM displays high structural and regional selectivity, which might play an important role in controlling the biological activities of this molecule.

Amino Acid Sequence↗
PubMed1998

Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors.

Neural cell adhesion molecules (NCAM) represent specific markers of neuroendocrine (NE) differentiation in lung cancer. Because the polysialic acid form (NCAM-PSA) has reduced adhesion properties, we hypothesized that NCAM-PSA expression could favor metastatic spread. Immunostaining of NCAM and NCAM-PSA were therefore compared in 120 NE lung tumors, including 17 typical carcinoids, 3 atypical carcinoids, 30 large cell NE carcinomas and 70 small cell lung carcinomas, as compared with 25 adenocarcinomas and 25 squamous cell carcinomas. Neural cell adhesion molecules were negative in adenocarcinomas and squamous cell carcinomas but were constantly expressed in all NE tumors from typical carcinoids to small cell lung carcinomas. NCAM-PSA expression was significantly more frequent in high-grade tumors, with 24 of 30 positive cases in large cell NE carcinomas and 65 of 70 positive cases in small cell lung carcinoma, than in carcinoids with 10 of 17 and 2 of 3 positive cases in typical carcinoids and atypical carcinoids, respectively. The neural cell adhesion molecule-polysialic acid form scores of staining were significantly higher in high-grade as compared with low-grade tumors (p = 0.002), and were correlated with nodal spread (p = 0.04) and metastasis (p = 0.016) across histologic classes but not in individual tumor type. We conclude that NCAM-PSA connotes poor differentiation and aggressive clinical behavior in the spectrum of NE lung tumors, but cannot be regarded as a prognostic factor in individual tumor classes.

Adenocarcinoma↗
PubMed2001

Overexpression of neural cell adhesion molecule in Chagas' myocarditis.

The expression of the neural cell adhesion molecule (NCAM) was studied in normal human myocardium and in Chagas' disease myocarditis. We found that NCAM is expressed in the conduction system as well as the myocardium in the fetal heart, but its expression is restricted to the conduction system and absent in the adult myocardium. Chagas' disease is an American endemic disease caused by the Trypanosoma cruzi parasite, which produces myocarditis and a blockade of the conduction system, resulting in cardiac dysfunction. We studied the expression of NCAM in paraffin-embedded human heart tissues from 34 autopsies of patients with Chagas' myocarditis and from murine and canine experimental acute Chagas' myocarditis, using a polyclonal anti-NCAM antibody and immunohistochemistry. Our results show a dramatic upregulation of NCAM expression in the intercalated discs of cardiomyocytes in acute and chronic Chagas' myocarditis. Surprisingly, the NCAM signal was detected in intracellular nests of amastigote forms of the parasite, within infected cardiomyocytes of human and experimental Chagas' myocarditis. In contrast, cardiac cell-cell adhesion proteins, N-cadherin and beta-catenin, were found in intercalated discs distorted by the infection but absent from the amastigote nests. Proteins reactive to several antibodies against NCAM were detected by Western immunoblotting in cultured T cruzi parasites and in trypomastigote forms of T cruzi extracted from the blood of infected mice. The upregulation of NCAM in Chagas' myocarditis and the expression of NCAM or a NCAM-like protein by T cruzi suggest that NCAM may act as a receptor for tissue targeting and cellular invasion by T cruzi in Chagas' disease.

Animals↗
PubMed1993

Nerve-dependent expression of high polysialic acid neural cell adhesion molecule in neurohypophysial astrocytes of adult rats.

The adult hypothalamo-neurohypophysial system of the rat retains the capacity to express highly polysialylated isoforms of neural cell adhesion molecule normally expressed in developing tissues. Here we report that the expression of these isoforms in neurohypophysial astrocytes (pituicytes) may be regulated by neurosecretory cells. In the intact neurohypophysis a strong and homogeneously distributed immunostaining for the "embryonic", highly sialylated form of neural cell adhesion molecules was detected by light-microscopic immunocytochemistry. By electron-microscopy, both neurosecretory axons and pituicytes were immunoreactive for this isoform. However, in contrast to the rather uniform staining on nerve fibres, polysialic acid immunolabelling on glial surfaces was uneven: immunostaining could be observed on glial surfaces facing neuronal elements, but not at contact sites between pituicytes. In addition, most glial and neuronal elements were heavily and evenly labelled with the polyclonal antibody recognizing "total" neural cell adhesion molecule. Surgical transection of the hypophysial stalk, a procedure that eliminates descending neurosecretory axons from the neurohypophysis, resulted in the complete disappearance of polysialic immunoreactivity from the neurohypophysis. The electron-microscopic analysis confirmed that cell surfaces of pituicytes lacked this immunoreactivity after the lesion. When residual neurosecretory axons were observed following an incomplete lesion, immunoreactivity on axons and glial processes was maintained. Transection did not affect the distribution of "total" neural cell adhesion molecule. We postulate that the presence of neurosecretory axons in the neurohypophysis is necessary to maintain the capacity of pituicytes to express immunoreactivity for the polysialylated isoforms of neural cell adhesion molecule but not the neural cell adhesion molecule itself since immunoreactivity for "total" neural cell adhesion molecule was unaltered after hypophysial stalk transection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb.

The highly sialylated isoform of the neural cell adhesion molecule is thought to be expressed predominantly in the developing nervous system, where it is implicated in a variety of dynamic events linked to neural morphogenesis. It has become increasingly evident, however, that this "embryonic" neural cell adhesion molecule isoform continues to be expressed in certain adult neuronal systems, and in particular, in those that can undergo structural plasticity. In the present study, we performed light microscopic immunocytochemistry with an antibody specific for polysialylated neural cell adhesion molecule and confirmed our earlier observations [Bonfanti L. et al. (1992) Neuroscience 49, 419-436] showing polysialylated neural cell adhesion molecule-immunoreactive cells in the subependymal layer of the lateral ventricle of the adult rat, a region where cell proliferation continues into the postnatal period. In addition, we used an antibody raised against the proliferating cell nuclear antigen and found that proliferating cells continue to be visible in this area, even in the adult. Double immunolabeling showed that many of these newly generated cells displayed high polysialylated neural cell adhesion molecule immunoreactivity. Cells from a portion of the subependymal layer migrate to the olfactory bulb and contribute to the continual replacement of its granule neurons [Luskin M. B. (1993) Neuron 11, 173-189]. We found polysialylated neural cell adhesion molecule-immunoreactive cells all along the pathway purported to be followed by the newly generated cells to their final destination and in neurons corresponding to granular and periglomerular cells in the olfactory bulb. Our present observations thus support the contention that polysialylation is a feature of neurons capable of dynamic change and may contribute to the molecular mechanisms permitting cell proliferation and migration not only during development but also in the adult.

Animals↗
PubMed1992

Mapping of the distribution of polysialylated neural cell adhesion molecule throughout the central nervous system of the adult rat: an immunohistochemical study.

In the nervous system, the neural cell adhesion molecule changes at the cell surface during development, from a form highly enriched in polysialic residues to several isoforms containing much less sialic acid, and is thought to participate in the structuring of neuronal groups and in the establishment of neuronal connections. Recent observations have indicated, however, that it may not be restricted to developing tissues since it is still present in certain adult neuronal centres which can undergo morphological reorganization. In this study, therefore, we examined systematically the distribution of polysialylated neural cell adhesion molecule immunoreactivity throughout the central nervous system of adult male and female rats, using light microscopic immunocytochemistry and immunoblot analysis with an antibody that specifically recognizes the polysialic residues of the molecule. Concomitantly, we compared this immunoreactivity to that due to all isoforms of the neural cell adhesion molecule, detected with a polyclonal serum raised against the NH2-terminal of the protein. Immunoreactivity due to the polysialylated isoform was consistently visualized in several discrete areas of the adult brain and spinal cord. An intercellular punctate immunolabelling characterized the staining in certain hypothalamic and thalamic nuclei, superficial laminae of the dorsal horn of the spinal cord, ventral portion of the dentate gyrus of the hippocampus, lateral geniculate, parabrachial and habenular nuclei, bed nucleus of the stria terminalis, mesencephalic central gray and olfactory bulb. In other areas, such as the piriform cortex, dorsal aspect of the dentate gyrus and fimbria and lamina X of the spinal cord, isolated neuronal-like cells were either completely filled with immunolabel or showed a surface reaction on their cell bodies and processes. Highly immunoreactive isolated glial-like cells were also noted within the ependymal layer of the central canal and lateral ventricles and at times in the peripheral white matter of the spinal cord. In contrast to this discrete localization, staining due to all isoforms of the neural cell adhesion molecule was widespread and diffuse throughout the brain and spinal cord. The expression of the polysialylated isoform in the supraoptic nucleus and hippocampus was confirmed by immunoblot analysis; it occurred together with weakly sialylated isoforms. No obvious differences were detected in the amount or distribution of immunoreactivity due to the polysialylated isoform in relation to the sex or age of the animals (between three and 12 months of age). Our study thus demonstrates that well-defined areas of the central nervous system of the adult rat continue to express the polysialylated isoform of the neural cell adhesion molecule.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Localization of mRNA for neural cell adhesion molecule (N-CAM) polypeptides in neural and nonneural tissues by in situ hybridization.

The differential expression of the mRNA for the neural cell adhesion molecule (N-CAM) has been studied by in situ hybridization and compared with protein localization analyzed by immunohistochemical staining. The distribution of mRNA during chicken embryonic development was analyzed in neural and nonneural tissues by using an RNA probe that detects all N-CAM mRNAs and a probe specific for the mRNA of the large cytoplasmic domain (ld) of N-CAM. The results provide a detailed description of the mRNA distribution for N-CAM. The distribution of mRNA for total N-CAM generally corresponded to that of protein but differed at a more detailed level of analysis. For example, the mRNA was localized only within the cell bodies of neurons, whereas the protein was also in neuronal processes; this differential localization was most clearly seen in the alternating layers of cell bodies and fibers in the optic tectum and cerebellum. N-CAM ld mRNA, which arises from alternative RNA splicing, was expressed only in neural tissues, confirming previous biochemical and histological studies. Differential expression of the ld mRNA was detected in specific neural cell types: N-CAM mRNA was present in the ependymal cells of the spinal cord and optic tectum, but mRNA for the ld form was absent. In contrast, the ld mRNA was among the N-CAM mRNAs found in the Purkinje cells and internal granule cells in the cerebellum. The differential expression of mRNAs for the N-CAM forms emphasizes the potential importance of alternative mRNA splicing in modulating adhesive events during embryonic development, particularly in the nervous system.

Animals↗
PubMed1999

Subtle roles of neural cell adhesion molecule and myelin-associated glycoprotein during Schwann cell spiralling in P0-deficient mice.

Peripheral nerves of P0-deficient mice display a severe dysmyelinating phenotype, confirming the view that P0 mediates myelin formation and compaction. In addition to the compromised myelin organization, an elevated expression of several cell recognition molecules was described in the axon-Schwann cell units of P0-deficient mice. The present study was performed to focus on the subcellular localization and functional roles of two of these up-regulated molecules, the neural cell adhesion molecule (N-CAM) and the myelin-associated glycoprotein (MAG). We show by postembedding immunoelectron microscopy that in peripheral nerves of P0-deficient mice both molecules are expressed in noncompacted myelin-like regions. In addition, N-CAM, but not MAG, is detected in partially compacted myelin. By the generation of P0/N-CAM- and P0/MAG-deficient double mutants, we investigated the roles of the dysregulated molecules in P0-deficient mice. In 4-week-old double mutants, the dysmyelinating phenotype of the axon-Schwann cell units was very similar to that seen in the P0-deficient single mutants, suggesting that neither N-CAM nor MAG are responsible for the poor myelin compaction in P0-deficient mice. However, the noncompacted turns surrounding the abnormally compacted regions were significantly reduced in number in P0/MAG mutants as compared to P0 or N-CAM/P0 mice. During formation of myelin sheaths, absence of N-CAM resulted in a transient retardation of Schwann cell spiralling in P0-deficient mice, whereas absence of MAG impaired Schwann cell spiralling for a more extended time period. Our findings demonstrate for the first time that MAG and also N-CAM can play significant roles during myelin formation in the peripheral nervous system. Because these functional roles are detectable only in the absence of P0, our results confirm the view that myelin-related molecules can play distinct, but also partially overlapping roles.

Animals↗
PubMed2001

Polysialylated neural cell adhesion molecule is involved in the neuroplasticity induced by axonal injury in the avian ciliary ganglion.

We demonstrated previously in the quail ciliary ganglion, that the immunoreactivity for the neural cell adhesion molecule labeling the postsynaptic specializations of intraganglionic synapses decreases when synaptic remodeling is induced by crushing the postganglionic ciliary nerves. Here we show, in the same experimental conditions, that the immunolabeling for its polysialylated non-stabilizing isoform, which promotes cell plasticity, increases at these subcellular compartments. In control ganglia, poor immunolabeling for the polysialylated neural cell adhesion molecule was occasionally observed surrounding the soma of the ciliary neurons, in correspondence with the calyciform presynaptic ending and the perineuronal satellite cells sheath. At the electron microscope, several neuronal compartments, including some postsynaptic specializations, somatic spines and multivesicular bodies, were immunopositive. Three to six days after ciliary nerve crush, both the number of ciliary neurons labeled for the polysialylated neural cell adhesion molecule and the intensity of their immunolabeling increased markedly. Electron microscopy revealed that, in parallel to the injury-induced detachment of the preganglionic boutons, numerous postsynaptic specializations were found to be immunopositive. Twenty days later, when intraganglionic connections were re-established, polysialylated neural cell adhesion molecule immunoreactivity was comparable to that observed in control ganglia. The increase in immunolabeling also involved the other neuronal compartments mentioned above, the perineuronal satellite cells and the intercellular space between these and the ciliary neurons. From these results we suggest that the switch, at the postsynaptic specializations, between the neural cell adhesion molecule and its polysialylated form may be among the molecular changes occurring in axotomized neurons leading to injury-induced synaptic remodeling. Moreover, from the increase in polysialylated neural cell adhesion molecule immunolabeling, observed at the somatic spines and at the interface between neurons and perineuronal satellite cells, we suggest that this molecule may be involved not only in synaptic remodeling, but also in other more general aspects of injury-induced neuronal plasticity.

Animals↗
PubMed2004

Reduced GABAergic transmission and number of hippocampal perisomatic inhibitory synapses in juvenile mice deficient in the neural cell adhesion molecule L1.

Cell adhesion molecules have been implicated in neural development and hippocampal synaptic plasticity. Here, we investigated the role of the neural cell adhesion molecule L1 in regulation of basal synaptic transmission and plasticity in the CA1 area of the hippocampus of juvenile mice. We show that theta-burst stimulation (TBS) and pairing of low-frequency presynaptic stimulation with depolarization of postsynaptic CA1 pyramidal cells induced similar levels of LTP in L1-deficient and wild-type mice. The basal excitatory synaptic transmission and density of asymmetric excitatory synapses in the stratum radiatum were also normal in L1-deficient mice. Since L1 is expressed not only by principal cells but also by inhibitory interneurons, we recorded inhibitory postsynaptic currents (IPSCs) evoked in CA1 pyramidal cells by minimal stimulation of perisomatic interneurons. L1-deficient mice showed a reduction in the mean amplitude of putative unitary IPSCs, higher values of the coefficient of amplitude variation, higher number of failures in transmitter release, and a reduction in frequency but not amplitude of miniature IPSCs. The use-dependent modulation of inhibitory transmission by paired-pulse or short tetanic stimulation was, however, normal in L1-deficient mice. The physiological abnormalities correlated with a strong reduction in the density of inhibitory active zones, indicating that L1 is involved in establishing inhibitory perisomatic synapses in the hippocampus.

Animals↗
PubMed1989

Embryonic neural cell adhesion molecules on human natural killer cells.

The neural cell adhesion molecules (NCAM) are surface glycoproteins that were first described in brain tissue. NCAM mediate adhesion in a variety of cell-cell interactions. In the present study we show that the so-called "embryonic" NCAM, i.e., the highly polysialylated forms of these proteins, are expressed on natural killer cells and some CD3+ cells in man. Homotypic binding of NCAM, believed to be of importance for cell-cell adhesion in neural tissues, appears not to be essential for NK cell-mediated killing. Yet, NCAM might be involved in NK cell migration, homing or related functions.

Antibodies, Monoclonal↗
PubMed1994

The homophilic binding site of the neural cell adhesion molecule NCAM is directly involved in promoting neurite outgrowth from cultured neural retinal cells.

The neural cell adhesion molecule NCAM mediates intercellular adhesion by homophilic binding and its homophilic binding site has been mapped to a decapeptide sequence 243-KYSFNYDGSE-252 located within the third immunoglobulin-like domain of chick NCAM. To investigate the relationship between homophilic binding and NCAM-dependent neurite outgrowth, mutations were created in the binding site of NCAM-140 cDNA. Mutant NCAMs were expressed in L cells, and their ability to promote neurite outgrowth from chick retinal ganglion cells was assayed in coculture systems. Mutations that resulted in the loss of NCAM homophilic binding failed to promote neurite outgrowth from retinal cells. Alternatively, synthetic peptides containing the decapeptide sequence of the homophilic binding site were used to block NCAM homophilic interaction. Peptides that inhibited NCAM-NCAM binding also blocked neurite elongation. However, the peptide P5 (243-KYSFNYDGSELIIKKVDKSDE-263), despite being an inhibitor of NCAM-NCAM binding, induced the sprouting of multiple neurites. Moreover, peptide P5 stimulated a 2-fold increase in neurite-bearing cells, suggesting that P5 is a potent inducer of neurite outgrowth. Only E4-E6 retinal cells could be induced by P5, corresponding closely to their NCAM-responsive embryonic stages. The P5 effects were inhibited by pertussis toxin, indicating the involvement of a G-protein-dependent pathway. Taken together, these results provide evidence for a direct role of the NCAM homophilic binding site in the regulation of neurite outgrowth.

Amino Acid Sequence↗
PubMed1990

The neural cell adhesion molecule N-CAM enhances L1-dependent cell-cell interactions.

On neural cells, the cell adhesion molecule L1 is generally found coexpressed with N-CAM. The two molecules have been suggested, but not directly shown, to affect each other's function. To investigate the possible functional relationship between the two molecules, we have characterized the adhesive interactions between the purified molecules and between cultured cells expressing them. Latex beads were coated with purified L1 and found to aggregate slowly. N-CAM-coated beads did not aggregate, but did so after addition of heparin. Beads coated with both L1 and N-CAM aggregated better than L1-coated beads. Strongest aggregation was achieved when L1-coated beads were incubated together with beads carrying both L1 and N-CAM. In a binding assay, the complex of L1 and N-CAM bound strongly to immobilized L1, but not to the cell adhesion molecules J1 or myelin-associated glycoprotein. N-CAM alone did not bind to these glycoproteins. Cerebellar neurones adhered to and sent out processes on L1 immobilized on nitrocellulose. N-CAM was less effective as substrate. Neurones interacted most efficiently with the immobilized complex of L1 and N-CAM. They adhered to this complex even when its concentration was at least 10 times lower than the lowest concentration of L1 found to promote adhesion. The complex became adhesive for cells only when the two glycoproteins were preincubated together for approximately 30 min before their immobilization on nitrocellulose. The adhesive properties between cells that express L1 only or both L1 and N-CAM were also studied. ESb-MP cells, which are L1-positive, but N-CAM negative, aggregated slowly under low Ca2+. Their aggregation could be completely inhibited by antibodies to L1 and enhanced by addition of soluble N-CAM to the cells before aggregation. N2A cells, which are L1 and N-CAM positive aggregated well under low Ca2+. Their aggregation was partially inhibited by either L1 or N-CAM antibodies and almost completely by the combination of both antibodies. N2A and ESb-MP cells coaggregated rapidly and their interaction was similarly inhibited by L1 and N-CAM antibodies. These results indicate that L1 is involved in two types of binding mechanisms. In one type, L1 serves as its own receptor with slow binding kinetics. In the other, L1 is modulated in the presence of N-CAM on one cell (cis-binding) to form a more potent receptor complex for L1 on another cell (trans-binding).

Animals↗
PubMed2007

Gangliogenesis in the enteric nervous system: roles of the polysialylation of the neural cell adhesion molecule and its regulation by bone morphogenetic protein-4.

The neural crest-derived cells that colonize the fetal bowel become patterned into two ganglionated plexuses. The hypothesis that bone morphogenetic proteins (BMPs) promote ganglionation by regulating neural cell adhesion molecule (NCAM) polysialylation was tested. Transcripts encoding the sialyltransferases, ST8Sia IV (PST) and ST8Sia II (STX), which polysialylate NCAM, were detectable in fetal rat gut by E12 but were downregulated postnatally. PSA-NCAM-immunoreactive neuron numbers, but not those of NCAM, were developmentally regulated similarly. Circular smooth muscle was transiently (E16-20) PSA-NCAM-immunoreactive when it is traversed by migrating precursors of submucosal neurons. Neurons developing in vitro from crest-derived cells immunoselected at E12 with antibodies to p75(NTR) expressed NCAM and PSA-NCAM. BMP-4 promoted neuronal NCAM polysialylation and clustering. N-butanoylmannosamine, which blocks NCAM polysialylation, but not N-propanoylmannosamine, which does not, interfered with BMP-4-induced neuronal clustering. Observations suggest that BMP signaling enhances NCAM polysialylation, which allows precursors to migrate and form ganglionic aggregates during the remodeling of the developing ENS.

Animals↗
PubMed2000

The human neural cell adhesion molecule L1 functions as a costimulatory molecule in T cell activation.

L1 is a neural cell adhesion molecule (CAM) known to be important for normal neurological development. Despite being described as a neural CAM, we have documented L1 expression by antigen-presenting cells of myelomonocytic origin. Here we demonstrate that L1 can function as a costimulatory molecule in T cell activation. A monoclonal antibody that abrogates L1-L1 homophilic binding significantly reduced mixed leukocyte responses initiated by allogeneic L1+ dendritic cells. Autologous T cell activation in response to phytohemagglutinin was also inhibited by blockade of L1. In accordance with these results, transfection of human L1 into a murine myeloma cell line significantly increased the capacity of these cells to stimulate xenogeneic T cell responses. As a costimulatory ligand L1 could represent a novel target for immunotherapeutic intervention and may act as an important intermediary in neuroimmunological processes and disease.

Animals↗