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PubMed1985

A developmental study of the biosynthesis of the neural cell adhesion molecule.

The neural cell adhesion molecule (N-CAM) is a glycoprotein found in neurons, glial cells and muscle cells. In this report we describe developmental changes in biosynthesis of N-CAM polypeptides in rat forebrain explant cultures. N-CAM was synthesized as the following polypeptides: HMr (Mr between 250,000 and 350,000), A (200,000 Mr), B (135,000 Mr) and C (115,000 Mr). The biosynthetic pattern of N-CAM polypeptides changed during development: the biosynthesis of HMr and C increased relative to A and B. N-CAM biosynthesis decreased 100-fold from embryonic day 17 to postnatal day 25; N-CAM turnover decreased 350-fold during the same period. N-CAM polysialylation and sulfatation decreased markedly with age, whereas phosphorylation seemed to be constant during development. Only polypeptides A and B were phosphorylated, whereas A, B and C were sulfated. A was more sulfated and phosphorylated than B. It is concluded that the above described modulations of N-CAM may be of importance in the developmental regulation of cell-cell adhesion.

Age Factors↗
PubMed1986

Rapid axonal transport of the neural cell adhesion molecule.

The neural cell adhesion molecule (NCAM) is a cell-surface glycoprotein that mediates cell-cell interactions in the nervous system during development. In the present study, we demonstrate that NCAM is axonally transported in 3-d-old chick retinal ganglion cells and that it travels within the fast component of axonal transport (FC). Proteins were radiolabeled in retinal ganglion cell bodies after intraocular injection of 35S-methionine. The presence of radiolabeled NCAM in the optic nerves and contralateral tecta was detected by specific immunoadsorption to a monoclonal antibody. Major radioactive polypeptide bands at relative mobilities of approximately 200,000, 150,000, and 120,000 Mr (after SDS-PAGE) were recognized by the anti-NCAM antibody. These bands comigrated in 1-dimensional gels with components of purified NCAM from chick brain. The 2 largest NCAM polypeptides (at 200,000 and 150,000 Mr) were found to be transported in this system, while the 120,000 Mr form was apparently not transported. The ratio and electrophoretic profiles of the 2 transported forms of NCAM remained similar in the retina, optic nerve, chiasm, tract, and tectum, suggesting that there is no interconversion of the 2 major polypeptides. The fraction of NCAM in the 35S-labeled FC proteins appears to be at least an order of magnitude less than in the plasma membrane, suggesting that the turnover rate of NCAM at this age is slower than for other membrane proteins of the CNS.

Animals↗
PubMed1985

Structural and functional studies on N-CAM neural cell adhesion molecules.

The neural cell adhesion molecules N-CAM are to date the best characterized adhesion molecules of the nervous system. They have a high content of sialic acid residues which are present in the form of unusual sialic acid polymers. During development, a 3 fold decrease in the sialic acid content is observed. These changes in the degree of sialylation profoundly affect the binding properties of the molecules. A subpopulation of mouse brain N-CAM bears a carbohydrate determinant shared with other brain cell surface proteins and with the HNK-1 antigen of natural killer cells. Not only the carbohydrate side chains but also the protein moieties of the N-CAMs are heterogeneous. Three polypeptides of 180 K, 140 K and 120 K have been characterized in mouse brain. The 180 K and 140 K chains span the membrane. They differ mainly by the length of their cytoplasmic extensions. These intracellular domains are unusually long and contain phosphorylated serine residues. The 120 K chain exists in two forms, one membrane-bound and one soluble. Earlier studies had shown the presence of N-CAM on neurones and astrocytes of the mouse central nervous system, whereas cultured astrocytes had been reported to be N-CAM-negative. Recent results show that N-CAM is also expressed on astrocytes in culture. To study expression and heterogeneity of N-CAM polypeptides at the mRNA and gene level, cDNA clones for mouse N-CAM have been isolated. They reveal multiple mRNA species in mouse brain. By contrast, the corresponding sequences seem to be present only a few times, perhaps only once, in the mouse genome.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Organization and reorganization of neuromuscular junctions in mice lacking neural cell adhesion molecule, tenascin-C, or fibroblast growth factor-5.

Many proteins have been hypothesized to mediate intercellular interactions that regulate the formation, maturation, and maintenance of the skeletal neuromuscular junction. Three of the best characterized of these are a membrane-associated adhesion molecule, neural cell adhesion molecule (N-CAM), an extracellular matrix component, tenascin-C, and a soluble growth factor, fibroblast growth factor-5 (FGF-5). To assess the roles of these molecules in synaptogenesis in vivo, we examined neuromuscular junctions in homozygous mutant mice lacking N-CAM, tenascin-C, FGF-5, or both N-CAM and tenascin-C. End plates were 14% smaller in N-CAM-deficient mice than in controls, and formation of junctional folds was delayed in this mutant. In all other respects tested, however, the structure and molecular architecture of neuromuscular junctions were normal in all three single mutants and in the double mutant. We also tested the abilities of damaged motor axons to reinnervate mutant muscle after axotomy and of intact motor axons to sprout after partial denervation. Again, no significant differences among genotypes were observed. Together, these results demonstrate that N-CAM, tenascin-C, and FGF-5 are dispensable for major aspects of synaptic development and regeneration.

Animals↗
PubMed1986

Oligodendrocyte cell adhesion molecules are related to neural cell adhesion molecule (N-CAM).

The glycoproteins responsible for calcium-dependent oligodendrocyte aggregation were purified and characterized. Using detergent extraction, lentil-lectin-Sepharose 4B affinity chromatography, and preparative gel electrophoresis, 3 proteins were purified to apparent homogeneity, with relative Mrs of 120,000, 140,000, and 180,000. The aggregation assay showed that all 3 proteins had the ability to block antibody-mediated inhibition of oligodendrocyte aggregation. The 120,000 protein was the most active of the three. Antisera were raised in rabbits to these 3 individual proteins. Western blot analyses showed that all three antisera recognized 120,000, 140,000, and 180,000 proteins, which indicated that the proteins were related. Western-blot analyses of cultured oligodendrocytes and purified rat myelin showed only the 120,000 protein. Immunoprecipitation of iodinated membrane proteins of cultured oligodendrocytes also indicated the presence of only the 120,000 Mr protein. Deglycosylation of the 120,000 protein by N-glycanase resulted in a 110,000 protein. The immunoblot pattern suggested some similarities between oligodendrocyte adhesion molecules and the neural cell adhesion molecule (N-CAM). Therefore, the 120,000, 140,000, and 180,000 Mr proteins were compared to N-CAM by Western-blot analysis, immunofluorescence staining, and by immunoprecipitation. The results suggest that oligodendrocytes contain a 120,000 membrane glycoprotein that is related to N-CAM.

Animals↗
PubMed2003

The cell adhesion molecules N-cadherin and neural cell adhesion molecule regulate human growth hormone: a novel mechanism for regulating pituitary hormone secretion.

Pituitary GH secretion is regulated by hypothalamic hormones and peripheral factors. Cell-cell contact may also have an important role in regulating pituitary hormone expression and secretion. The role of pituicyte cell-cell contact mediated by N-cadherin and neural cell adhesion molecule (N-CAM) was studied in the regulation of GH secretion. RT-PCR showed N-cadherin mRNA expression in eight of 12 of GH-secreting adenomas compared with one of seven of prolactin-cell adenomas. N-cadherin and N-CAM were similarly expressed in adenomas and in adult and fetal normal pituitary tissues. The effects of CAM homophilic binding on GH secretion from dispersed human fetal pituitary cultures were studied by manipulating CAM mediated cell-cell contact using either soluble N-cadherin-Fc or pituitary cells cocultured with NIH-3T3 cells stably expressing CAMs. CAM stimulation increased GH secretion from pituitary fetal cultures by 40-60% (P < 0.05) and also from cultured GH adenoma cells by 40-75% (P < 0.05). Disrupting N-cadherin homophilic binding by anti-N-cadherin antibody decreased fetal, but not tumorous GH secretion by 40% (P < 0.05). This study indicates that pituitary cell-cell contact mediated by homophilic interactions between adhesion molecules regulates human GH secretion.

3T3 Cells↗
PubMed1998

Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1.

BACKGROUND: Neural cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been implicated in both the fasciculation and guidance of axons, but direct genetic evidence of a role for neural IgCAMs in axon guidance in vertebrates is lacking. The L1 subfamily of vertebrate neural IgCAMs function as both homophilic and heterophilic receptors for a variety of cell-surface and extracellular ligands and may signal through intracellular kinases or by recruitment of the fibroblast growth factor receptor. L1 itself has been implicated in many neural processes and is expressed widely in the embryonic and adult nervous systems. In humans, mutations in the L1 gene are linked with a spectrum of brain disorders, including loss of the corticospinal tract, but the mechanistic basis for these disorders is unknown. RESULTS: We show that mice that do not express L1 have defects in the guidance of axons of the corticospinal tract, a major motor control pathway projecting from the cortex to the spinal cord. Although the pathway to the caudal medulla appears normal, a substantial proportion of axons fail to cross the midline to the opposite dorsal column as normal. In adults, this results in a reduced decussation and in large numbers of axons projecting ipsilaterally. There is also a varying, but reduced, number of corticospinal axons in the dorsal columns of the spinal cord. These do not project beyond cervical levels. We show that these are defects in axon guidance, because they arise during the early stages of the development of the decussation. The presence of a ligand for L1, CD24, specifically at the point of decussation suggests a mechanism in which L1 functions to guide corticospinal axons across the midline. CONCLUSIONS: L1 function is necessary for the guidance of corticospinal axons across the pyramidal decussation in mice. Some of the defects in the corticospinal tract of humans with mutations in L1 could be due to errors in axon guidance at the pyramidal decussation.

Animals↗
PubMed1997

Developmentally regulated masking of an intracellular epitope of the 180 kDa isoform of the neural cell adhesion molecule NCAM.

The neural cell adhesion molecule NCAM is a cell surface glycoprotein that occurs in several isoforms. It was previously shown that the largest 180-kDa isoform of NCAM (NCAM 180) accumulates at sites of cell contact and in postsynaptic densities and may be responsible for the stabilization of cell contacts by its interaction with the membrane-cytoskeleton linker protein brain spectrin. In immunohistochemical studies on the expression of the NCAM 180, we noticed that two NCAM 180 specific monoclonal antibodies, termed 481 and D3, showed different patterns of immunoreactivity in sections of fresh-frozen adult mouse brain. Here we show that the D3-specific, but not the 481-specific epitope becomes inaccessible to the antibody during development of the hippocampal formation, coincident with the establishment of stable cell-cell contacts. In contrast, in the olfactory bulb with its continually regenerating olfactory nerve fibers, both NCAM 180 antibodies remain fully immunoreactive throughout development and adulthood. We also show that the D3-specific epitope becomes inaccessible in primary cerebellar neuron cultures with time in culture. Electrophoretic separation of hippocampal membrane proteins under nondenaturating conditions showed NCAM to be present in protein complexes of different molecular weights at different developmental stages. We propose that NCAM is involved in the formation of developmentally regulated, noncovalent complexes with as yet unknown partner molecules that could be responsible for the masking of the D3-specific epitope.

Animals↗
PubMed1999

Paucity of retinoic acid receptor alpha (RAR alpha) nuclear immunostaining in gliomas and inability of retinoic acid to influence neural cell adhesion molecule (NCAM) expression.

Neural cell adhesion molecule (NCAM) is down-regulated during periods of embryological cell migration and may be important in local tumor migration or metastases. Conflicting information exists in the literature about NCAM expression in human glial tumors and little is known about its expression in human brain metastases. We immunohistochemically stained a panel of 43 primary human brain tumors and their cultured counterparts for NCAM including glioblastoma multiformes, anaplastic astrocytomas, oligodendrogliomas, and contrasted their staining with a panel of 3 meningiomas, 11 brain metastases, and 5 normal brain samples utilizing the monoclonal antibody NKH-1. Most gliomas and metastatic melanomas and lung carcinomas showed a high percentage of cells positive for NCAM expression while NCAM staining was negative for other carcinomas. No difference was seen between intensity or percentage of cells that were NCAM positive, based on tumor grade or type. In glioma cell lines, NCAM expression was lost upon passage. In 15 glioma cell lines we also determined NCAM isoform expression by reverse transcription/polymerase chain reaction (RT/PCR) and found that 6 of 15 had message for NCAM 180, 8 of 15 for NCAM 140, and only 3 of 15 had message for NCAM 120. Normal brains always contained message for the 180 isoform and usually had mRNA for all 3 isoforms. Using monoclonal antibodies for retinoic acid receptor alpha (RAR alpha), we found nuclear staining in melanomas and lung carcinomas metastatic to brain and only rarely in gliomas. Neither the relative antigen density of NCAM nor the percent of NCAM-positive cells appreciably changed upon incubation with retinoic acid (RA), as measured by flow cytometry. RAR alpha was not found at a level measurable by immunohistochemistry in nuclei of most glial tumors, providing an explanation for why RA might not induce NCAM expression. Whether paucity of RAR alpha on primary gliomas might also correlate with results from clinical trials showing limited efficacy of RA in treatment of human gliomas awaits further study.

Brain↗
PubMed2001

Alternative mRNA splicing in colon cancer causes loss of expression of neural cell adhesion molecule.

BACKGROUND: The neural cell adhesion molecule (NCAM) has numerous isoforms resulting from alternative splicing of mRNA. The 3 major isoforms found in adult tissue are (1) a 120-kDa protein that is linked to the plasma membrane by glycosylphosphatidylinositol; (2) a 140-kDa form that has a transmembrane component and a cytoplasmic tail with unknown function; and (3) a 180-kDa isoform that has an intracellular protein that binds the cytoskeleton. NCAM is capable of homotypic binding and therefore plays a role in cell-cell adhesion for cells expressing the 180-kDa isoform by anchoring groups of cells into epithelial sheets. NCAM-180 is the isoform found in colonocytes, and loss of expression is associated with clinically aggressive colon cancers. METHODS: Western blotting and reverse transcriptase-polymerase chain reaction were used to screen commercially available cell lines for NCAM-180 expression. For cell-line pairs with differential NCAM-180 expression, exon analysis was performed with reverse transcriptase-polymerase chain reaction to determine where the molecule was spliced, culminating in failed expression. These results were confirmed with exon analysis in colon cancers harvested at the time of laparotomy. RESULTS: Analysis of a SW480 cell line (derived from a patient's primary colon cancer lesion) revealed NCAM-180 expression, whereas no expression was found in the SW620 cell line (derived from a metastatic lesion from the same patient). Exon analysis of NCAM mRNA transcripts from SW620 revealed that the transcripts were truncated after exon 12. This region correlates to an area between 2 fibronectin-III domains on the NCAM protein. CONCLUSIONS: The most common site for NCAM alternative splicing is between the 2 fibronectin-III domains corresponding to the border between exons 12 and 13 of the NCAM gene. Loss of NCAM-180 expression in aggressive colon carcinoma results from a splice defect in the same area, which may result in defective intracellular adhesion between colonocytes.

Alternative Splicing↗
PubMed2004

Backbone dynamics of the first, second, and third immunoglobulin modules of the neural cell adhesion molecule (NCAM).

The neural cell adhesion molecule (NCAM) is a cell surface multimodular protein, which plays an important role in cell-cell adhesion by homophilic (NCAM-NCAM) and heterophilic (NCAM-non-NCAM molecules) binding. In the present study, the backbone dynamics of the first three immunoglobulin-like (Ig) modules of NCAM have been investigated by NMR spectroscopy. Ig1, Ig2, and Ig3 share low sequence identity but possess the same fold and have very similar three-dimensional structures. (15)N longitudinal and transverse relaxation rates and heteronuclear NOEs have been measured and subsequently analyzed by the axial symmetric Lipari-Szabo modelfree formalism to characterize fast (pico- to nanosecond) and slow (micro- to millisecond) motions in the three protein modules. We found that backbone motions of residues located in the beta-strand regions are generally restricted, while increased flexibility is observed in turns and loops. In all three modules, residues located in the segments connecting the C- and D-strand plus residues located in the segment connecting the E- and F-strand show significant chemical exchange on the micro- to millisecond time scale. In addition, a number of residues with small chemical exchange contribution seem to form contiguous regions in the beta sheets, suggesting that these motions might be correlated. Only few residues in the homophilic binding sites in the NCAM Ig1 and Ig2 modules show increased flexibility, indicating that the Ig1-Ig2-mediated NCAM homophilic binding does not depend on the local backbone mobility of the interacting modules.

Binding Sites↗
PubMed2006

Reduced reactivity to novelty, impaired social behavior, and enhanced basal synaptic excitatory activity in perforant path projections to the dentate gyrus in young adult mice deficient in the neural cell adhesion molecule CHL1.

The neural cell adhesion molecule CHL1 is implicated in neural development in the mouse and has been related to psychiatric disorders in humans. Here we report that mice constitutively deficient for CHL1 display reduced reactivity to environmental stimuli and reduced expression of social behaviors, whereas cognitive, motor and olfactory functions are normal. Basal synaptic transmission and plasticity in seven major excitatory connections in the hippocampus were analyzed to test whether dysfunctions in this brain region, which controls complex behaviors, correlate with the behavioral alterations of CHL1 deficient mice. We found that basal synaptic transmission in lateral and medial perforant path projections to the dentate gyrus is elevated in CHL1-deficient mice. Taking in consideration the function of these synapses in processing information from cortical areas, we hypothesize that constitutive ablation of CHL1 leads to reduced capability to react to external stimuli due to dysfunctions in the dentate gyrus.

Animals↗
PubMed1997

Enhancement of neurite outgrowth by the soluble form of human L1 (neural cell adhesion molecule).

L1, a neural cell adhesion molecule, is involved in neurite outgrowth, migration and fasciculation. Although L1 is a membrane glycoprotein expressed on neural cells, the soluble form of L1 is generated in vivo by proteolysis. In the present study, a stable transfectant of Chinese hamster ovary (CHO) cells secreting human L1 without cytoplasmic and membrane spanning domains was generated, and the function of the secreted L1 was examined. Explants from embryonic chick brain stem were cultured on a substrate coated with polyethylenimine (PEI) alone, on substrate-bound L1 or in medium containing soluble L1. The neurites induced by L1, both the substrate-bound form and the soluble form, were 2-3 times longer than those cultured on PEI. The ability of the soluble L1 to induce neurite formation was slightly greater than that of the substrate L1. The present results demonstrated that neurite outgrowth was induced not only by substrate-bound L1 but also by soluble L1. Soluble L1 could be a pharmaceutical candidate for the promotion of nerve regeneration.

Animals↗
PubMed1992

Identification of a peptide sequence involved in homophilic binding in the neural cell adhesion molecule NCAM.

The neural cell adhesion molecule NCAM is capable of mediating cell-cell adhesion via homophilic interactions. In this study, three strategies have been combined to identify regions of NCAM that participate directly in NCAM-NCAM binding: analysis of domain deletion mutations, mapping of epitopes of monoclonal antibodies, and use of synthetic peptides to inhibit NCAM activity. Studies on L cells transfected with NCAM mutant cDNAs using cell aggregation and NCAM-covasphere binding assays indicate that the third immunoglobulin-like domain is involved in homophilic binding. The epitopes of four monoclonal antibodies that have been previously shown to affect cell-cell adhesion mediated by NCAM were also mapped to domain 3. Overlapping hexapeptides were synthesized on plastic pins and assayed for binding with these monoclonal antibodies. One of them (PP) reacted specifically with the sequence KYSFNY. Synthetic oligopeptides containing the PP epitope were potent and specific inhibitors of NCAM binding activity. A substratum containing immobilized peptide conjugates also exhibited adhesiveness for neural retinal cells. Cell attachment was specifically inhibited by peptides that contained the PP-epitope and by anti-NCAM univalent antibodies. The shortest active peptide has the sequence KYSFNYDGSE, suggesting that this site is directly involved in NCAM homophilic interaction.

Amino Acid Sequence↗
PubMed1992

Developmental regulation of alternative splicing in the mRNA encoding Xenopus laevis neural cell adhesion molecule (NCAM).

The neural cell adhesion molecule (NCAM) is thought to play a role in the formation of the vertebrate nervous system. In mammals and chicken, it is known that more than 100 different forms of the NCAM protein can be generated by alternative splicing of one primary transcript and it is possible that these different forms have distinct biological functions. A large part of the diversity is generated by alternative mRNA splicing in two regions, called the pi and the muscle specific domain (MSD), that encode portions of the extracellular domain of the NCAM protein. In this report, we describe the tissue and developmental expression of the pi and MSD sequences in the amphibian, Xenopus laevis. Our experiments show that NCAM transcripts are present in all tissues examined including muscle, heart, liver, kidney, and brain. We have identified a 30-base exon, similar to the pi domain observed in mammals, that is not present in maternal NCAM RNA but appears in a subset of the NCAM mRNA population shortly after neural induction. At the predicted location of the MSD we have detected only two alternatively spliced exons, 3 bases and 15 bases in length. In no X. laevis tissue examined did we detect the two additional alternatively spliced exons which are present in the MSD region of mammalian and chicken NCAM RNAs. Finally, the analysis has revealed a dynamic and complex pattern of expression of alternatively spliced NCAM mRNAs during embryogenesis. High levels of expression of specific forms of NCAM RNA correlate with major morphogenic events such as neural tube formation and metamorphosis.

Amino Acid Sequence↗
PubMed1986

Phosphatidylinositol is involved in the membrane attachment of NCAM-120, the smallest component of the neural cell adhesion molecule.

The rodent neural cell adhesion molecule (NCAM) consists of three glycoproteins with Mr of 180,000, 140,000 and 120,000. The Mr 120,000 protein (NCAM-120) has been shown to exist in membrane-bound and soluble forms but the nature of its membrane association and release has remained obscure. We show here that phosphatidylinositol-specific phospholipase C (PI-PLC), but not a phospholipase C of different specificity, releases a substantial proportion of NCAM-120 from brain membranes and solubilizes almost quantitatively NCAM-120 present at the surface of C6 astroglial cells. The PI-PLC effect was highly selective since only one other protein species was detectably released from C6 cells. These results suggest that NCAM-120 is held in the membrane by covalently bound phosphatidylinositol or a closely related lipid in a way similar to several other surface proteins from eukaryotic cells. The presence of NCAM in a form which can be released from the cell surface by a highly selective mechanism raises additional possibilities for modulation and control of cell--cell adhesion.

Animals↗
PubMed1994

Characterization of Pax-6 and Hoxa-1 binding to the promoter region of the neural cell adhesion molecule L1.

The neural cell adhesion molecule L1, a member of the immunoglobulin superfamily, mediates cell interactions in the developing and regenerating nervous system of mammals and is also detectable in the immune system and in the epithelia of intestine, skin, lung, and kidney. This diverse pattern of expression begs the question as to the regulatory mechanisms underlying transcription of the L1 gene. We demonstrate here that the paired domain and homeodomain containing Pax-6 protein binds to three different sites in the promoter region of the L1 gene. The promoter proximal binding site is also recognized by Hoxa-1 and lies approximately 60 bp upstream from the transcription start site only few base pairs upstream of a putative binding site for the TFII-I transcription initiation factor. On the basis of this sequence, we have characterized the binding of Pax-6 and explored two modes of its DNA binding activities.

Base Sequence↗
PubMed1989

Primary structure and developmental expression of a large cytoplasmic domain form of Xenopus laevis neural cell adhesion molecule (NCAM).

The neural cell adhesion molecule, (NCAM), is involved in cell-cell interactions during development of the vertebrate nervous system. NCAM exists in multiple protein forms and these are selectively expressed in different cells and at different times during development. Here we report the complete amino acid sequence of the large cytoplasmic form of Xenopus laevis NCAM, derived from a full-length cDNA clone. Using specific probes the expression of different NCAM transcripts during Xenopus embryogenesis has been examined. We find that transcripts encoding the large cytoplasmic domain form of NCAM exist in maternal RNA and that these are the only significant NCAM transcripts present until late gastrula when transcripts encoding the small cytoplasmic domain form of NCAM are first detected. No RNA encoding the small surface domain form of NCAM is detected during early development. These results indicate that the expression of NCAM sequences during early development of Xenopus differs from that described in other species.

Amino Acid Sequence↗