Alternative titles; symbols
HGNC Approved Gene Symbol: CD9
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,199,946-6,238,266 (from NCBI)
Using a murine monoclonal antibody (602-29), Andrews et al. (1981) identified a chromosome 12-determined surface antigen. Andrews et al. (1982) studied a murine monoclonal antibody that recognizes an antigen expressed by most, but not all, human cells and by none of 14 different murine tumor cell lines. The antigenic determinant was found to be carried by a polypeptide with an apparent molecular weight of 21,000. Goodfellow (1982) referred to the antigen as MIC3; M for monoclonal, IC for Imperial Cancer Research Fund, and 3 for their third. CD9 is also known as the p24 antigen because it is a protein of molecular weight 24 kD.
Boucheix et al. (1991) estimated the size of CD9 mRNA to be 1.4 kb. The CD9 antigen appeared to be a 227-amino acid molecule with 4 hydrophobic domains and 1 N-glycosylation site. Sequence and structural comparisons showed extensive similarity to the 237-amino acid molecule described as the human melanoma-associated antigen ME491. These proteins identify a new family of cell-surface proteins.
Pregnancy-specific glycoproteins (PSGs; see 176390) are placentally secreted members of the carcinoembryonic antigen (see CEACAM1; 109770) family whose concentration in blood increases exponentially until term. Low levels of PSGs are associated with pathologic conditions such as spontaneous abortion, intrauterine growth retardation, and preeclampsia. There are several human PSGs, and the mouse PSGs are numbered Psg14 to Psg30. By screening a mouse macrophage cDNA expression library with mouse Psg17, Waterhouse et al. (2002) identified the tetraspanin Cd9 as its receptor. Binding could be inhibited by anti-Cd9, and Psg17 did not bind any other tetraspanins tested. The authors stated that Cd9 is the first identified partner for a PSG family member and that Psg17 is the first identified ligand of a tetraspanin.
Using immunoprecipitation analysis, Sharma et al. (2008) showed that ZDHHC2 (618621) expression specifically and selectively promoted palmitoylation of the tetraspanins CD9 and CD151 (602243) and thereby enhanced CD9-CD151 association. Knockdown of ZDHHC2 in HEK293 cells resulted in loss of CD9 and CD151 palmitoylation, enhanced lysosomal proteolysis and degradation and CD9 and CD151, and cell dispersion.
Using human cord blood CD34 (142230)-positive hematopoietic stem cells (HSCs), Leung et al. (2011) showed that SDF1 (CXCL12; 600835) stimulation through CXCR4 (162643) enhanced CD9 expression. Blocking CD9 inhibited transendothelial migration and calcium mobilization, whereas adhesion to fibronectin and endothelial cells was enhanced. Anti-CD9 treatment of HSCs impaired homing of the cells to immunodeficient mouse bone marrow and spleen. CD9-negative HSCs displayed lower bone marrow homing capacity compared with total HSCs. CD9 expression was upregulated in homed HSCs in vivo. Leung et al. (2011) proposed that CD9 has a role in HSC homing.
Lazareth et al. (2019) showed that expression of Cd9 markedly increased glomerulus invasion by parietal epithelial cells in mouse models of crescentic glomerulonephritis and focal segmental glomerulosclerosis. The authors also observed increased expression of CD9 in kidneys of patients diagnosed with these disorders. Expression of CD9 was detected by both RNA sequencing comparisons of healthy versus diseased glomeruli and by immunohistochemistry. Deletion of Cd9 in mice offered protection against glomerular damage.
By study of mouse-human cell hybrids, the CD9 gene was found to reside on chromosome 12 (Andrews et al., 1982). Katz et al. (1983) also mapped the gene encoding BA-2/p24 to chromosome 12 by the expression of the monoclonal antibody-defined cell surface antigen in hybrid cells. Van Cong et al. (1989) assigned the gene to 12p13 by Southern analysis of hybrid cell DNA and by in situ hybridization; also see Benoit et al. (1991).
Le Naour et al. (2000) generated CD9 -/- mice by targeted disruption. Homozygous adult CD9 -/- mice showed no obvious abnormalities and appeared healthy. However, CD9 -/- females displayed a severe reduction of fertility. Oocytes were ovulated but were not successfully fertilized because sperm did not fuse with the oocytes from CD9 -/- females. Le Naour et al. (2000) concluded that CD9 appears to be essential for sperm-egg fusion, a process involving the CD9-associated integrin alpha-6/beta-1.
Miyado et al. (2000) independently generated mice lacking CD9 by homologous recombination. Both male and female CD9 -/- mice were born healthy and grew normally. However, the litter size from CD9 -/- females was less than 2% that of wildtype. In vitro fertilization experiments indicated that the cause of this infertility was due to the failure of sperm-egg fusion. When sperm were injected into oocytes by assisted microfertilization techniques, however, the fertilized eggs developed to term. Miyado et al. (2000) thus confirmed that CD9 is crucial for sperm-egg fusion. They also found that CD9 physically associates with integrin alpha-6/beta-1 on the egg plasma membrane and suggested that integrin alpha-6/beta-1 may transduce signals to CD9 and initiate or otherwise promote fusion.
The cell-surface molecule CD9, a member of the transmembrane-4 superfamily, interacts with the integrin family and other membrane proteins, and is postulated to participate in cell migration and adhesion. Expression of CD9 enhances membrane fusion between muscle cells (Tachibana and Hemler, 1999) and promotes viral infection in some cells. Fertilization also involves membrane fusion, between gametes. In mammals, the sperm binds to microvilli on the egg surface, and the sperm-egg membrane fusion first occurs around the equatorial region of the sperm head. The fused membrane is then disrupted and the sperm nucleus as well as the cytoplasm is incorporated into the egg. Cd9 is expressed on the plasma membrane of the mouse egg, and an anti-Cd9 monoclonal antibody inhibits sperm-egg surface interactions. Kaji et al. (2000) generated Cd9 -/- mice and found that homozygous mutant females were infertile. The sperm-egg binding was normal, but sperm-egg fusion was almost entirely inhibited in eggs from Cd9 -/- females. Intracellular Ca(2+) oscillations, which signal fertilization, were absent in almost all mutant eggs; in rare cases, a response occurred after a long time period. In normal animals, Cd9 molecules were expressed on the egg microvilli and became densely concentrated at the sperm attachment site. Thus, the results of Kaji et al. (2000) showed that CD9 is important in the gamete fusion process at fertilization.
Rubinstein et al. (2006) observed a 40% reduction in fertility in Cd81 (186845) -/- female mice, but not Cd81 -/- male mice, similar to the rate observed in Cd9 -/- female mice. The reduced fertility occurred in spite of normal mating behavior, access to sperm, and normal ovaries. Postnatal survival of Cd81 -/- mice was low. Female mice lacking both Cd9 and Cd81 were all infertile, whereas heterozygotes had normal fertility. In vitro fertilization experiments showed that fusion did not occur in Cd9 -/- oocytes and was rare in Cd81 -/- oocytes. In contrast with anti-Cd9 antibodies, no tested anti-Cd81 antibodies blocked sperm-egg fusion. Rubinstein et al. (2006) concluded that CD81 and CD9 are involved in sperm-egg fusion.
By means of mouse monoclonal antibodies derived after immunization with human tumor cells or melanocytes, Dracopoli et al. (1984) identified 2 cell surface antigens (MSK4; MSK7) that mapped to 12q, and 1 (MSK3, antigen identified by monoclonal antibody M68) that mapped to 12p. (The development of the monoclonal antibodies at the Sloan-Kettering Cancer Center is responsible for the designations.)
Andrews, P. W., Knowles, B. B., Goodfellow, P. N. A human cell-surface antigen defined by a monoclonal antibody and controlled by a gene on chromosome 12. Somat. Cell Genet. 7: 435-443, 1981. [PubMed: 6792721] [Full Text: https://doi.org/10.1007/BF01542988]
Andrews, P. W., Knowles, B. B., Goodfellow, P. N. A chromosome 12-controlled cell surface antigen defined by a monoclonal antibody. (Abstract) Cytogenet. Cell Genet. 32: 249 only, 1982.
Benoit, P., Gross, M. S., Frachet, P., Frezal, J., Uzan, G., Boucheix, C., Van Cong, N. Assignment of the human CD9 gene to chromosome 12 (region p13) by use of human specific DNA probes. Hum. Genet. 86: 268-272, 1991. [PubMed: 1997380] [Full Text: https://doi.org/10.1007/BF00202407]
Boucheix, C., Benoit, P., Frachet, P., Billard, M., Worthington, R. E., Gagnon, J., Uzan, G. Molecular cloning of the CD9 antigen: a new family of cell surface proteins. J. Biol. Chem. 266: 117-122, 1991. [PubMed: 1840589]
Dracopoli, N. C., Rettig, W. J., Goetzger, T. A., Houghton, A. N., Spengler, B. A., Oettgen, H. F., Biedler, J. L., Old, L. J. Three human cell surface antigen systems determined by genes on chromosome 12. Somat. Cell Molec. Genet. 10: 475-481, 1984. [PubMed: 6206575] [Full Text: https://doi.org/10.1007/BF01534852]
Goodfellow, P. N. Personal Communication. London, England 1982.
Kaji, K., Oda, S., Shikano, T., Ohnuki, T., Uematsu, Y., Sakagami, J., Tada, N., Miyazaki, S., Kudo, A. The gamete fusion process is defective in eggs of Cd9-deficient mice. Nature Genet. 24: 279-282, 2000. [PubMed: 10700183] [Full Text: https://doi.org/10.1038/73502]
Katz, F., Povey, S., Parkar, M., Schneider, C., Sutherland, R., Stanley, K., Solomon, E., Greaves, M. Chromosome assignment of monoclonal antibody-defined determinants on human leukemic cells. Europ. J. Immun. 13: 1008-1013, 1983. [PubMed: 6198179] [Full Text: https://doi.org/10.1002/eji.1830131211]
Lazareth, H., Henique, C., Lenoir, O., Puelles, V. G., Flamant, M., Bollee, G., Fligny, C., Camus, M., Guyonnet, L., Millien, C., Gaillard, F., Chipont, A., and 21 others. The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression. Nature Commun. 10: 3303, 2019. Note: Electronic Article. [PubMed: 31341160] [Full Text: https://doi.org/10.1038/s41467-019-11013-2]
Le Naour, F., Rubinstein, E., Jasmin, C., Prenant, M., Boucheix, C. Severely reduced female fertility in CD9-deficient mice. Science 287: 319-321, 2000. [PubMed: 10634790] [Full Text: https://doi.org/10.1126/science.287.5451.319]
Leung, K. T., Chan, K. Y. Y., Ng, P. C., Lau, T. K., Chiu, W. M., Tsang, K. S., Li, C. K., Kong, C. K. L., Li, K. The tetraspanin CD9 regulates migration, adhesion, and homing of human cord blood CD34+ hematopoietic stem and progenitor cells. Blood 117: 1840-1850, 2011. [PubMed: 21063023] [Full Text: https://doi.org/10.1182/blood-2010-04-281329]
Miyado, K., Yamada, G., Yamada, S., Hasuwa, H., Nakamura, Y., Ryu, F., Suzuki, K., Kosai, K., Inoue, K., Ogura, A., Okabe, M., Mekada, E. Requirement of CD9 on the egg plasma membrane for fertilization. Science 287: 321-324, 2000. [PubMed: 10634791] [Full Text: https://doi.org/10.1126/science.287.5451.321]
Rubinstein, E., Ziyyat, A., Prenant, M., Wrobel, E., Wolf, J.-P., Levy, S., Le Naour, F., Boucheix, C. Reduced fertility of female mice lacking CD81. Dev. Biol. 290: 351-358, 2006. [PubMed: 16380109] [Full Text: https://doi.org/10.1016/j.ydbio.2005.11.031]
Sharma, C., Yang, X. H., Hemler, M. E. DHHC2 affects palmitoylation, stability, and functions of tetraspanins CD9 and CD151. Molec. Biol. Cell 19: 3415-3425, 2008. [PubMed: 18508921] [Full Text: https://doi.org/10.1091/mbc.e07-11-1164]
Tachibana, I., Hemler, M. E. Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J. Cell Biol. 146: 893-904, 1999. [PubMed: 10459022] [Full Text: https://doi.org/10.1083/jcb.146.4.893]
Van Cong, N., Benoit, P., Gross, M. S., Uzan, G., Frachet, P., Marguerie, G., Frezal, J., Boucheix, C. Assignment of the gene for CD9 (p24) antigen to 12p13. (Abstract) Cytogenet. Cell Genet. 51: 1096 only, 1989.
Waterhouse, R., Ha, C., Dveksler, G. S. Murine CD9 is the receptor for pregnancy-specific glycoprotein 17. J. Exp. Med. 195: 277-282, 2002. [PubMed: 11805154] [Full Text: https://doi.org/10.1084/jem.20011741]