Alternative titles; symbols
HGNC Approved Gene Symbol: NCAM1
Cytogenetic location: 11q23.2 Genomic coordinates (GRCh38): 11:112,961,420-113,278,436 (from NCBI)
Great structural diversity in NCAM is due to transcriptional variations of a single gene and posttranslational mechanisms which are under exquisite developmental control (Rutishauser and Goridis, 1986). The neural cell adhesion molecule appears on early embryonic cells and is important in the formation of cell collectives and their boundaries at sites of morphogenesis. Later in development it is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle.
NCAM shares many features with immunoglobulins and is considered a member of the immunoglobulin superfamily. Cunningham et al. (1987) determined the structure of the 3 polypeptides of chicken NCAM; the chains are called ld, sd, and ssd.
Lin et al. (1994) stated that there are cell adhesion molecules in invertebrates related to NCAM. Fasciclin II has been cloned in grasshoppers and Drosophila; apCAM has been identified in Aplysia. In these species, the NCAM analogs are members of the immunoglobulin superfamily both in structure (5 C2-type immunoglobulin domains followed by 2 fibronectin type 3 domains) and sequence. All of these molecules can mediate homophilic cell aggregation in vitro. Lin et al. (1994) used loss-of-function and gain-of-function mutants of fasciclin II in Drosophila to study the protein's function during growth cone guidance. The fasciclin II mutants had impaired fasciculation, but other aspects of outgrowth and directional guidance were intact, and thus genetically separate.
NCAM is a membrane-bound glycoprotein that plays a role in cell-cell and cell-matrix adhesion through both its homophilic and heterophilic binding activity. To investigate the significance of this binding, Rabinowitz et al. (1996) used a gene targeting strategy in embryonic stem (ES) cells to replace the membrane-associated form of NCAM with a soluble, secreted form of its extracellular domain. Although the heterozygous mutant ES cells were able to generate low coat color chimeric mice, only the wildtype allele was transmitted, suggesting the possibility of dominant lethality. Analysis of chimeric embryos with a high level of ES cell contribution revealed severe growth retardation and morphologic defects by embryonic days 8.5-9.5. The second allele was also targeted and embryos derived almost entirely from the homozygous mutant ES cells exhibited the same lethal phenotype as observed with heterozygous chimeras.
Rubinek et al. (2003) studied the role of pituicyte cell-cell contact mediated by CDH2 (114020) and NCAM1 in the regulation of GH (139250) secretion. RT-PCR showed CDH2 mRNA expression in 8 of 12 GH-secreting adenomas compared with 1 of 7 prolactin-cell adenomas. CDH2 and NCAM1 were similarly expressed in adenomas and in adult and fetal normal pituitary tissues. Cell adhesion molecule (CAM) stimulation increased GH secretion from pituitary fetal cultures by 40 to 60% and also from cultured GH adenoma cells by 40 to 75%. Disrupting CDH2 homophilic binding by anti-CDH2 antibody decreased fetal, but not tumorous, GH secretion by 40%. This study indicated that pituitary cell-cell contact mediated by homophilic interactions between adhesion molecules regulates human GH secretion.
Lievens et al. (2016) reported that mouse Zdhhc3 (617150) catalyzed S-palmitoylation of the transmembrane isoforms of Ncam1, Ncam140 and Ncam180. Using site-directed mutagenesis and inhibitor studies, they showed that Fgf2 (134920) induced phosphorylation of Zdhhc3 on tyr18 via the tyrosine kinase activity of its receptor, Fgfr1 (136350). Src (190090) directly phosphorylated Zdhhc3 on tyr295 and tyr297. The 2 kinases had opposite effects on Zdhhc3 activity, with Fgfr1-dependent phosphorylation enhancing Zdhhc3 activity, and Src-dependent phosphorylation inhibiting Zdhhc3 activity. Autopalmitoylation, an intermediate reaction state in palmitate transfer to target proteins, was enhanced by absence of all 5 tyrosines in Zdhhc3 and was abolished with the dominant-negative cys157-to-ser (C157S) mutation at the active site of Zdhhc3. Overexpression of tyrosine-mutant Zdhhc3 in cultured rat hippocampal neurons increased the number of neurites and tended to increase neurite length. Lievens et al. (2016) concluded that FGF2-FGFR1 signaling facilitates ZDHHC3 tyrosine phosphorylation and triggers NCAM1 palmitoylation for neurite extension, whereas SRC-mediated ZDHHC3 phosphorylation inhibits NCAM1 palmitoylation and neurite extension.
Because of evidence indicating close homology of neural cell adhesion molecule (NCAM) in man and mouse, a murine cDNA probe for NCAM could be used directly for in situ hybridization to human metaphase chromosomes (Nguyen et al., 1985). This procedure indicated that the NCAM gene is located at 11q22-q23. Mietus-Snyder et al. (1989) corroborated the location of the NCAM gene to the 11q23 region by finding linkage to the apolipoprotein gene cluster, APOA1--APOC3--APOA4 (107680, 107720, 107690); a maximum lod score of 3.65 at theta = 0.10 was observed. Further studies by Mietus-Snyder et al. (1990) showed a maximum lod score of 15.9 at a recombination fraction of 0.028.
D'Eustachio et al. (1985) mapped the NCAM gene to mouse chromosome 9 by means of a genomic probe in somatic cell hybrids. The gene is close to 2 others on mouse 9 whose expression is related to the nervous system, namely Thy1 (see 188230 for the human counterpart) and the cerebellar connectional mutant 'staggerer' (sg; see 600825); NCAM-associated DNA polymorphisms were used in recombinant inbred strains of mice to show these linkages as well as close linkage to Sep1 (apolipoprotein-1) and Lap1 (leucine aminopeptidase-1).
Bello et al. (1989) sublocalized the NCAM gene to 11q23.1 by in situ hybridization to pachytene bivalents. Because of the close mapping of the 'staggerer' mutation with the Ncam locus in the mouse, it was earlier thought that the sg mutation might involve the Ncam locus. By demonstrating recombination between the 2 loci, D'Eustachio and Davisson (1993) proved that the murine neurologic disease is not due to mutation in the NCAM protein. By linkage analysis and pulsed field gel electrophoresis, Telatar et al. (1995) mapped the NCAM gene to 11q23, proximal to the locus for dopamine receptor D2 (DRD2; 126450).
Bello, M. J., Salagnon, N., Rey, J. A., Guichaoua, M. R., Berge-Lefranc, J. L., Jordan, B. R., Luciani, J. M. Precise in situ localization of NCAM, ETS1, and D11S29 on human meiotic chromosomes. Cytogenet. Cell Genet. 52: 7-10, 1989. [PubMed: 2612216] [Full Text: https://doi.org/10.1159/000132828]
Cunningham, B. A., Hemperly, J. J., Murray, B. A., Prediger, E. A., Brackenbury, R., Edelman, G. M. Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science 236: 799-806, 1987. [PubMed: 3576199] [Full Text: https://doi.org/10.1126/science.3576199]
D'Eustachio, P., Davisson, M. T. Resolution of the staggerer (sg) mutation from the neural cell adhesion molecule locus (Ncam) on mouse chromosome 9. Mammalian Genome 4: 278-280, 1993. [PubMed: 8507983] [Full Text: https://doi.org/10.1007/BF00417436]
D'Eustachio, P., Owens, G. C., Edelman, G. M., Cunningham, B. A. Chromosomal location of the gene encoding the neural cell adhesion molecule (N-CAM) in the mouse. Proc. Nat. Acad. Sci. 82: 7631-7635, 1985. [PubMed: 3865183] [Full Text: https://doi.org/10.1073/pnas.82.22.7631]
Lievens, P. M.-J., Kuznetsova, T., Kochlasmazashvili, G., Cesca, F., Gorinski, N., Galil, D. A., Cherkas, V., Ronkina, N., Lafera, J., Gaestel, M., Ponimaskin, E. ZDHHC3 tyrosine phosphorylation regulates neural cell adhesion molecule palmitoylation. Molec. Cell. Biol. 36: 2208-2225, 2016. [PubMed: 27247265] [Full Text: https://doi.org/10.1128/MCB.00144-16]
Lin, D. M., Fetter, R. D., Kopczynski, C., Grenningloh, G., Goodman, C. S. Genetic analysis of fasciclin II in Drosophila: defasciculation, refasciculation, and altered fasciculation. Neuron 13: 1055-1069, 1994. [PubMed: 7946345] [Full Text: https://doi.org/10.1016/0896-6273(94)90045-0]
Mietus-Snyder, M., Charmley, P., Korf, B., Ladias, J. A. A. Gatti, R. A. and Karathanasis, S. K.: Genetic linkage of the human apolipoprotein AI-CIII-AIV gene cluster and the neural cell adhesion molecule (NCAM) gene. Genomics 7: 633-637, 1990. [PubMed: 1974882] [Full Text: https://doi.org/10.1016/0888-7543(90)90211-c]
Mietus-Snyder, M., Korf, B., Ladias, J. A., Karathanasis, S. K. Linkage of the human apolipoproteins A1, C3, A4 and the neural cell adhesion molecule (NCAM) genes. (Abstract) Cytogenet. Cell Genet. 51: 1044 only, 1989.
Nguyen, C., Mattei, M. G., Goridis, C., Mattei, J. F., Jordan, B. R. Localization of the human N-CAM gene to chromosome 11 by in situ hybridization with a murine N-CAM cDNA probe. (Abstract) Cytogenet. Cell Genet. 40: 713 only, 1985.
Nguyen, C., Mattei, M. G., Mattei, J.-F., Santoni, M.-J., Goridis, C., Jordan, B. R. Localization of the human NCAM gene to band q23 of chromosome 11: the third gene coding for a cell interaction molecule mapped to the distal portion of the long arm of chromosome 11. J. Cell Biol. 102: 711-715, 1986. [PubMed: 2869046] [Full Text: https://doi.org/10.1083/jcb.102.3.711]
Rabinowitz, J. E., Rutishauser, U., Magnuson, T. Targeted mutation of Ncam to produce a secreted molecule results in a dominant embryonic lethality. Proc. Nat. Acad. Sci. 93: 6421-6424, 1996. [PubMed: 8692830] [Full Text: https://doi.org/10.1073/pnas.93.13.6421]
Rettig, W. J. Chromosome assignment of the human 5.1H11 and E3 cell surface antigens. (Abstract) Cytogenet. Cell Genet. 51: 1065-1066, 1989.
Rubinek, T., Yu, R., Hadani, M., Barkai, G., Nass, D., Melmed, S., Shimon, I. The cell adhesion molecules N-cadherin and neural cell adhesion molecule regulate human growth hormone: a novel mechanism for regulating pituitary hormone secretion. J. Clin. Endocr. Metab. 88: 3724-3730, 2003. [PubMed: 12915661] [Full Text: https://doi.org/10.1210/jc.2003-030090]
Rutishauser, U., Acheson, A., Hall, A. K., Mann, D. M., Sunshine, J. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 240: 53-57, 1988. [PubMed: 3281256] [Full Text: https://doi.org/10.1126/science.3281256]
Rutishauser, U., Goridis, C. NCAM: the molecule and its genetics. Trends Genet. 2: 72-76, 1986.
Telatar, M., Lange, E., Uhrhammer, N., Gatti, R. A. New localization of NCAM, proximal to DRD2 at chromosome 11q23. Mammalian Genome 6: 59-60, 1995. [PubMed: 7719033] [Full Text: https://doi.org/10.1007/BF00350901]