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PubMed2000

Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity.

Functional properties of the neural cell adhesion molecule (NCAM) are strongly influenced by polysialylation. We used gene-targeting to generate mice lacking ST8SiaIV/PST-1, one of the polysialyltransferases responsible for addition of polysialic acid (PSA) to NCAM. Mice homozygous for the null mutation reveal normal development of gross anatomical features. In contrast to NCAM-deficient mice, olfactory precursor cells in the rostral migratory stream express PSA and follow their normal pathway. Furthermore, delamination of mossy fibers in the hippocampal CA3 region, as found in NCAM-deficient mice, does not occur in ST8SiaIV mutants. However, during postnatal development these animals show a decrease of PSA in most brain regions compared to wild-type animals. Loss of PSA in the presence of NCAM protein but in the absence of obvious histological changes allowed us to directly address the role of PSA in synaptic plasticity. Schaffer collateral-CA1 synapses, which express PSA in wild types, showed impaired long-term potentiation (LTP) and long-term depression (LTD) in adult mutants. This impairment was age-dependent, following the time course of developmental disappearance of PSA. Contrary to NCAM mutant mice, LTP in ST8SiaIV mutants was undisturbed at mossy fiber-CA3 synapses, which do not express PSA in wild-type mice. The results demonstrate an essential role for ST8SiaIV in synaptic plasticity in hippocampal CA1 synapses, whereas PSA produced by different polysialyltransferase or polysialyltransferases at early stages of differentiation regulates migration of neural precursor cells and correct lamination of mossy fibers. We suggest that NCAM but not PSA is likely to be important for LTP in the hippocampal CA3 region.

Aging↗

PubMed1991

Removal of C6 astrocytoma cell surface molecules with phosphatidylinositol phospholipase C: effect on regulation of neural cell adhesion molecule isoforms.

Different membrane-associated isoforms of the neural cell adhesion molecules have been described. One of them, N-CAM120, has been shown to be anchored to the membranes by a complex glycan-phosphatidylinositol group and to be releasable, under soluble form, by the bacterial enzyme phosphatidylinositol-phospholipase C. We used the C6 rat astrocytoma cell line expressing both N-CAM120 and the transmembrane isoform N-CAM140 as a model system. We investigated whether artificial depletion of cell membrane N-CAM120 influences the synthesis and the messenger RNA transcript levels of the isoforms of the neural cell adhesion molecules. Our results showed an increase in the rate of N-CAM120 protein synthesis, whereas the expression of N-CAM140 decreased. Additionally, perturbations in the levels of the 6.7-kb messenger RNA encoding for N-CAM140 were observed, whereas the 2.7-kb transcript encoding for N-CAM120 remained stable. Examination of the time course for the reexpression of N-CAM120 showed that control levels were recovered after 24 h. We provide evidence that N-CAM120 spontaneously released in the culture medium is not incorporated into the extracellular matrix; however, its concentration is important because, if the medium was changed, cells rapidly released a new pool.

Animals↗

PubMed1988

Effects of altered expression of the neural cell adhesion molecule, N-CAM, on early neural development in Xenopus embryos.

The neural cell adhesion molecule, N-CAM, is known to be expressed very early in the development of the vertebrate nervous system. In frog embryos, N-CAM expression increases dramatically in ectoderm coincident with the formation of the neural plate and tube, suggesting that morphogenesis of the early nervous system is controlled in part by differential expression of N-CAM. This model was tested by introducing synthetic N-CAM transcripts into Xenopus embryos so that N-CAM was indiscriminately expressed at high levels on the surface of both induced and noninduced ectodermal cells throughout gastrulation and neurulation. Analysis of these embryos shows that high levels of N-CAM misexpression do not effect neural tube formation even though ectopic expression of N-CAM in epidermis and somitic mesoderm caused specific defects in the structure of these tissues. By showing that the properly regulated expression of N-CAM is not essential for neural tube formation, these results provide compelling evidence that N-CAM on its own does not act as a regulatory molecule during early neural development.

Animals↗

PubMed1997

Cellular determinants of the lateral mobility of neural cell adhesion molecules.

The lateral mobility of the neural cell adhesion molecule (NCAM) was examined using fluorescence recovery after photobleaching (FRAP). Various isoforms of human NCAM, differing in their ectodomain, their membrane anchorage mode or in the size of their cytoplasmic domain, were expressed in NIH 3T3 cells and C2C12 muscle cells. When the various isoforms were compared in 3T3 cells, FRAP studies showed both GPI-anchored and transmembrane isoforms diffused rapidly and only small differences in either the diffusion coefficients (D) or the mobile fractions (mf) were measured, suggesting the importance of the ectodomain in regulating lateral diffusion. However, the mobility of all NCAM isoforms was greatly reduced in regions of cell-cell contact, presumably due to homophilic trans interactions between NCAMs on adjacent cells. NCAM isoforms transfected into C2C12 cells which express NCAM naturally usually displayed a significantly lower D compared to the same isoforms transfected into 3T3 cells. Thus, NCAM lateral mobility is modulated in regions where cells interact and by the structure of the host cell membrane.

3T3 Cells↗

PubMed1995

Neural cell adhesion molecule expression in human pituitary adenomas.

Neural cell adhesion molecule (NCAM) is a cell surface glycoprotein whose expression may be important in metastatic or local growth of neoplasms. Expression of NCAM in human pituitary adenomas was assessed on snap-frozen and Bouin's and/or formalin-fixed, paraffin-embedded archival tissue using a sensitive alkaline phosphatase-antialkaline phosphatase method of immunostaining with the monoclonal antibody, NKH-1. The 20 pituitary adenoma patients consisted of 13 males and 7 females, ages 19-78 years, with null cell macroadenomas (3), plurihormonal macroadenomas (4), weak gonadotropic macroadenomas (5), growth hormone-prolactin adenomas (2), and prolactinomas (6). Eight of the adenomas were clinically invasive. The snap-frozen material from 14 pituitary tumors showed immunostaining for NCAM in either a cytoplasmic, peripheral membranous, or mixed pattern; 2 of 3 prolactinomas showed patchy immunostaining. The Bouin's and/or formalin-fixed pituitary adenoma specimens from 6 clinically invasive cases showed less distinct NCAM localization but 4 out of 6 showed diffusely positive NCAM immunostaining, with greatest intensity appreciated on the Bouin's-fixed tissue. There was no correlation between NCAM staining pattern and invasive characteristics of the tumors. These results suggest that NCAM expressivity is not a useful marker for assessing pituitary adenoma tumor invasiveness.

Adenoma↗

PubMed2002

Expression of the neural cell adhesion molecule during mouse tooth development.

The neural cell adhesion molecule (NCAM) is a molecule that mediates calcium-independent cell-cell adhesion, and is expressed during development in a variety of tissues including nonneuronal ones. Expression of NCAM during molar tooth development was analyzed in this present study. In the enamel organ, NCAM expression was detected from the embryonic day 13 onward in restricted areas, including a part of the stratum intermedium of the tooth germ at the bell stage. Mesenchymal cells also expressed NCAM from the bud stage of the first molar onward. In addition to the strong expression in the dental follicle, weak and transient expression was detected in the dental papilla. The second and the third molars appeared to initiate their development by the interaction between the epithelial cells and NCAM-expressing mesenchymal cells. Comparison of the expression patterns of NCAM and transcription factor Barx1 revealed a possibility that Barx1 negatively regulates NCAM expression.

Animals↗

PubMed1998

Intracellular location, temporal expression, and polysialylation of neural cell adhesion molecule in astrocytes in primary culture.

Neural cell adhesion molecules (NCAMs) constitute a group of cell surface glycoproteins that control cell-cell interactions and play important morphoregulatory roles in the developing and regenerating nervous system. NCAMs exist in a variety of isoforms differing in the cytoplasmic domain and/or their content in sialic acid. The highly sialylated form (PSA-NCAM) is expressed by neurons, whereas it is believed that the less sialylated NCAM forms are synthesised by astrocytes. Moreover, little is known about the molecular sequence of the events that contribute to its expression at the cell surface. Here we report that during the proliferation of cortical astrocytes, at 4 days in primary culture, these cells expressed PSA-NCAM as well as NCAM 180. Then, during cell differentiation these isoforms progressively disappeared and the NCAM 140 became predominant. By immunofluorescence and immunocytochemistry studies we also show that PSA-NCAM and NCAM are first observed in small cytoplasmic spots or vesicles, located in or near the Golgi apparatus, as demonstrated by their co-localization with labelled wheat germ agglutinin (WGA) in this cell organelle. Thereafter, immunostained cytoplasmic NCAM gradually disappeared and became detectable at the cell surface of differentiating astrocytes. We also describe for the first time sialyltransferase activity in these cells and report that the levels of this activity correlated with the decrease in PSA-NCAM expression during the differentiation of astrocytes. These results will contribute to our understanding of the PSA and NCAM intracellular transport pathways and their expression at the cell surface. Moreover, the presence of PSA-NCAM in astrocytes suggests their possible role in nerve branching, fasciculation, and synaptic plasticity.

Animals↗

PubMed1998

A role for polysialic acid in neural cell adhesion molecule heterophilic binding to proteoglycans.

The neural cell adhesion molecule (NCAM) is known to participate in both homophilic and heterophilic binding, the latter including mechanisms that involve interaction with proteoglycans. The polysialic acid (PSA) moiety of NCAM can serve as a negative regulator of homophilic binding, but indirect evidence has suggested that PSA can also be involved in heterophilic binding. We have examined this potential positive role for PSA in terms of the adhesion of PSA-expressing mouse F11 cells and chick embryonic brain cells to substrates composed of the purified heparan sulfate proteoglycans agrin and 6C4. This adhesion was specifically inhibited by polyclonal anti-NCAM Fab antibodies, monoclonal anti-PSA antibodies, PSA itself, and enzymatic removal of either PSA or heparan sulfate side chains. By contrast, the adhesion was not affected by chondroitinase, and cell binding to laminin was not inhibited by any of these treatments. A specific NCAM-heparan sulfate interaction in this adhesion was further indicated by its inhibition with monoclonal anti-NCAM Fab antibodies that recognize the known heparin-binding domain of NCAM and with the HBD-2 peptide derived from this region, but not with antibodies directed against other regions of the protein including the homophilic binding region. Together, the results suggest that PSA can act in vitro either as a receptor in NCAM heterophilic adhesion or as a promoter of binding between heparan sulfate proteoglycans and the NCAM heparin-binding domain.

Agrin↗

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↗

PubMed1996

Homophilic adhesion mediated by the neural cell adhesion molecule involves multiple immunoglobulin domains.

The neural cell adhesion molecule (N-CAM) mediates homophilic binding between a variety of cell types including neurons, neurons and glia, and neurons and muscle cells. The mechanism by which N-CAM on one cell interacts with N-CAM on another, however, is unknown. Attempts to identify which of the five immunoglobulin-like domains (Ig I-V) and the two fibronectin type III repeats (FnIII 1-2) in the extracellular region of N-CAM are involved in this process have led to ambiguous results. We have generated soluble recombinant proteins corresponding to each of the individual immunoglobulin domains and the combined FnIII 1-2 and prepared polyclonal antibodies specific for each. The purified proteins and antibodies were used in aggregation experiments with fluorescent microspheres and chicken embryo brain cells to determine possible contributions of each domain to homophilic adhesion. The recombinant domains were tested for their ability to bind to purified native N-CAM, to bind to each other, and to inhibit the aggregation of N-CAM on microspheres and the aggregation of neuronal cells. Each of the immunoglobulin domains bound to N-CAM, and in solution all of the immunoglobulin domains inhibited the aggregation of N-CAM-coated microspheres. Soluble Ig II, Ig III, and Ig IV inhibited neuronal aggregation; antibodies against whole N-CAM, the Ig III domain, and the Ig I domain all strongly inhibited neuronal aggregation, as well as the aggregation of N-CAM-coated microspheres. Of all the domains, the third immunoglobulin domain alone demonstrated the ability to self-aggregate, whereas Ig I bound to Ig V and Ig II bound to Ig IV. The combined FnIII 1-2 exhibited a slight ability to self-aggregate but did not bind to any of the immunoglobulin-like domains. These results suggest that N-CAM-N-CAM binding involves all five immunoglobulin domains and prompt the hypothesis that in homophilic cell-cell binding mediated by N-CAM these domains may interact pairwise in an antiparallel orientation.

Animals↗

PubMed1993

Lateral patterns of the neural cell adhesion molecule on the surface of hippocampal cells developing in vitro.

In monolayer cultures of hippocampal neurons from newborn rats, an immunocytochemical quantitative study was carried out to investigate age-dependent arrangement of the neural cell adhesion molecules in different parts of cell membranes. On the fifth and 12th day in vitro, neural cell adhesion molecules were labelled with specific antibodies and protein A conjugated to colloidal gold particles. Samples of randomly selected electron micrographs that displayed labelled membrane fragments of cell bodies, growth cones, and axons were numerically analysed for the five- and 12-day in vitro neurons. Neural cell adhesion molecules surface topography was quantitatively described and compared, using a statistical stereological approach. The mean surface density of labelled neural cell adhesion molecules was found to be approximately 2.5 times higher in growth cone membranes relative to somatic and axonal membranes in five-day in vitro neurons. By the 12th day in vitro, this density decreases in somatic membranes (approximately 18%) and increases in axonal membranes (approximately 60%). Representative spectra of lateral intervals between labels as well as images that show typical topography of label on membrane surfaces were simulated. The results revealed regular patterns of neural cell adhesion molecules on the somatic surface and allowed consideration of neural cell adhesion molecules arrangement in a view of membrane adhesion properties. Participation of cytoskeleton in neural cell adhesion molecules rearrangement is discussed.

Animals↗

PubMed2000

Differential expression of alternatively spliced neural cell adhesion molecule L1 isoforms during oligodendrocyte maturation.

The expression of neural cell adhesion molecules and myelin-specific molecules is precisely regulated according to cell type and developmental age. We investigated whether different isoforms of these molecules change during development of oligodendrocytes. Immature oligodendrocytes cultured from embryonic day 18 rat cerebrum were distinguished into early stage and late stage by morphological and immunocytochemical criteria. mRNA levels of the neural cell adhesion molecule L1 in late-stage immature oligodendrocytes were approximately fivefold higher than in early-stage cells, but early-stage immature oligodendrocytes predominantly expressed an L1 spliced isoform lacking two region (exon 2 and 27). Late-stage cells expressed full-length L1 identical to the neuronal form. mRNA for the neural cell adhesion molecules NCAM and MAG did not show any difference in expression pattern. These results suggest that alternatively spliced isoforms of L1 might be regulated by temporal and spatial factors during oligodendrocyte development.

Age Factors↗

PubMed2006

Increased polysialic acid neural cell adhesion molecule expression in human hippocampus of heroin addicts.

Chronic exposure to heroin is known to cause cognitive deficits. However, little is known about the underlying molecular mechanisms. It has been suggested that opiate-induced neurotoxicity as well as impaired plasticity and regeneration may be relevant. One of the target regions where regeneration still can be observed in the adult brain is the hippocampus. Since polysialic acid neural cell adhesion molecule is regarded as one of the key players involved in plasticity and regeneration of neural tissue, we analyzed polysialic acid neural cell adhesion molecule expression in the fascia dentate hilus of the human hippocampus of 29 lethally intoxicated heroin addicts and matched controls. Immunohistochemistry with an antibody directed against polysialic acid neural cell adhesion molecule revealed its expression in differently sized cells which could be identified as neurons and glial cells. We observed an increase in the percentage of polysialic acid neural cell adhesion molecule positive neurons in hippocampal hilus of heroin addicts compared with controls (P = 0.001).Interestingly, we also observed polysialic acid neural cell adhesion molecule expression in glial cells as evidenced by double immunofluorescence with glial fibrillary acidic protein and polysialic acid neural cell adhesion molecule using confocal laser scanning microscopy. The fraction of polysialic acid neural cell adhesion molecule positive glial cells was also higher in heroin addicts compared with controls (P = 0.009). In addition, within the group of addicts morphine blood concentrations showed a positive correlation with the percentage of polysialic acid neural cell adhesion molecule positive neurons (P = 0.04; r = 0.547). In conclusion, we observed an increase in polysialic acid neural cell adhesion molecule positive neurons and glial cells in hippocampi of heroin addicts. This might reflect an attempt to repair cell damage due to heroin exposure.

Adolescent↗

PubMed1996

Dorsal rhizotomy induces transient expression of the highly sialylated isoform of the neural cell adhesion molecule in neurons and astrocytes of the adult rat spinal cord.

Expression of the weakly adhesive, highly sialylated isoform of the neural cell adhesion molecule is a feature common to cell capable of migration and conformation changes. 11,18,19 Polysialylated neural cell adhesion molecule also intervenes in axonal outgrowth and synaptogenesis during development and after lesion. 11,13 High levels of polysialylated neural cell adhesion molecule immunoreactivity are normally visible in laminae I,II and X of the adult rat spinal cord. 2,15 We how here that unilateral cervical dorsal rhizotomy induced no detectable changes in immunoreactivity in these areas. However, 24 h after lesion, polysialylated neural cell adhesion molecule immunoreactivity appeared in neurons scattered in laminae III-IX, ipsi-and contralateral to lesion. This reaction increased particularly on the contralateral side, became maximal at four days and disappeared eight days later. At this time, there was immunolabelling of astrocytes with an activated morphology. The astrocytic labelling, predominant on the side ipsilateral to the lesion, was strongest 12 days after rhizotomy, then diminished progressively. Deafferentation thus causes a transient expression of polysialylated neural cell adhesion molecule within areas of the spinal cord distinct from those which permanently express this adhesion molecule. Such expression occurs both in neurons and glial cells, with a temporal pattern specific to each type of cell.

Afferent Pathways↗

PubMed1987

Changes in neural cell adhesion molecule (NCAM) structure during vertebrate neural development.

Changes in carbohydrate and polypeptide form of the neural cell adhesion molecule (NCAM) have been documented during the development of central nervous system tissue in both chicken and frog. The carbohydrate variations reflect a high and low content of polysialic acid, and for the two vertebrates examined the expression of these forms is similar. At very early stages of neural development NCAM with a low content of polysialic acid is present, during histogenesis of the central nervous system NCAM with a high content of polysialic acid dominates, and there is a gradual return to NCAM with a low content of polysialic acid as the animals approach maturity. In contrast, the order of expression of the major NCAM polypeptide forms is different in the chicken and frog. These findings suggest that changes in sialic acid are a fundamental aspect of the function of NCAM in development, whereas NCAM polypeptide differences may affect events associated with a particular vertebrate. Studies have demonstrated that a decreased sialic acid content enhances the adhesion properties of NCAM. On this basis, we propose that NCAM with a low content of polysialic acid functions both to maintain integrity of neuroepithelium during morphogenesis of the early embryo and to stabilize differentiated structures in the adult, while the decreased adhesive function of NCAM with a high content of polysialic acid provides more plasticity in cell interactions during cell migration, axon outgrowth, and formation of neural circuits.

Animals↗

PubMed2004

Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas.

BACKGROUND: Neural cell adhesion molecule; nerve growth factor; and its receptors TrkA, TrkB, TrkC, and p75(NGFR) regulate unique survival pathways in the cells of different noncutaneous malignancies exhibiting a perineural invasive phenotype. Their expression is currently unknown in basal cell carcinoma and cutaneous squamous cell carcinoma exhibiting perineural invasion. OBJECTIVE: The objective was to evaluate neural cell adhesion molecule, nerve growth factor, TrkA, TrkB, TrkC, and p75(NGFR) expression when perineural invasion occurs in basal cell carcinoma and cutaneous squamous cell carcinoma. METHODS: Four basal cell carcinomas and five cutaneous squamous cell carcinomas that were perineural invasion-positive and four basal cell carcinomas and three cutaneous squamous cell carcinomas that were perineural invasion-negative were evaluated for the expression of neural cell adhesion molecule, nerve growth factor, TrkA, TrkB, TrkC, and p75(NGFR) by immunohistochemical staining. RESULTS: For neural cell adhesion molecule, six of eight basal cell carcinomas and two of eight cutaneous squamous cell carcinomas stained positive. For nerve growth factor, seven of nine perineural invasion-positive and six of seven perineural invasion-negative tumors stained moderately or greater. For TrkA, B, and C, the perineural invasion-positive cutaneous squamous cell carcinomas generally stained darker than the perineural invasion-negative cutaneous squamous cell carcinomas. For p75(NGFR), four of five perineural invasion-positive cutaneous squamous cell carcinoma stain patterns indicated that p75(NGFR) expression was higher perineurally than elsewhere in the tumor. CONCLUSION: In basal cell carcinoma and cutaneous squamous cell carcinoma, the presence of neural cell adhesion molecule may determine tumor aggression and increased levels of nerve growth factor and TrkA, B, and C may reflect unique survival pathways. Higher levels of expression of Trk receptors in cutaneous squamous cell carcinoma cells may predict perineural invasion and the increased p75(NGFR) expression found in cutaneous squamous cell carcinoma perineurally may allow p75(NGFR) immunohistochemical staining to be used for detecting sites of perineural invasion.

Aged↗

PubMed1995

Regulated expression of the neural cell adhesion molecule L1 by specific patterns of neural impulses.

Development of the mammalian nervous system is regulated by neural impulse activity, but the molecular mechanisms are not well understood. If cell recognition molecules [for example, L1 and the neural cell adhesion molecule (NCAM)] were influenced by specific patterns of impulse activity, cell-cell interactions controlling nervous system structure could be regulated by nervous system function at critical stages of development. Low-frequency electrical pulses delivered to mouse sensory neurons in culture (0.1 hertz for 5 days) down-regulated expression of L1 messenger RNA and protein (but not NCAM). Fasciculation of neurites, adhesion of neuroblastoma cells, and the number of Schwann cells on neurites was reduced after 0.1-hertz stimulation, but higher frequencies or stimulation after synaptogenesis were without effect.

Animals↗

PubMedDate not supplied

Developmental biology of a neural cell adhesion molecule.

A membrane glycoprotein isolated from embryonic brain has been shown to be a ligand in the formation of cell-cell bonds. The molecule, called neural cell adhesion molecule (N-CAM), participates in several aspects of neural development, including the formation of plexiform layers, neurite fasciculation and nerve-muscle interactions. Experiments in vivo indicate that N-CAM-mediated adhesion is essential to the orderly assembly of the visual system.

Animals↗