Human-specific expression of Siglec-6 in the placenta
Abstract
CD33-related-Siglecs are lectins on immune cells that recognize sialic acids via extracellular domains, and deliver negative signals via cytosolic tyrosine-based regulatory motifs. We report that while Siglec-6/OB-BP1 (which can also bind leptin) is expressed on immune cells of both humans and the closely related great apes, placental trophoblast expression is human-specific, with little or no expression in ape placentae. Human-specific transcription factor recognition site changes in the Siglec-6 promoter region can help explain the human-specific expression. Human placenta also expresses natural ligands for Siglec-6 (a mixture of glycoproteins carrying cognate sialylated targets), in areas adjacent to Siglec-6 expression. Ligands were also found in uterine endometrium and on cell lines of trophoblastic or endometrial origin. Thus, Siglec-6 was recruited to placental expression during human evolution, presumably to interact with sialylated ligands for specific negative signaling functions and/or to regulate leptin availability. The control of human labor is poorly understood, but involves multiple cues, including placental signaling. Human birthing is also prolonged in comparison to that in our closest evolutionary relatives, the great apes. We found that Siglec-6 levels are generally low in placentae from elective surgical deliveries without known labor and the highest following completion of labor. We therefore speculate that the negative signaling potential of Siglec-6 was recruited to human-specific placental expression, to slow the tempo of the human birth process. The leptin-binding ability of Siglec-6 is also consistent with this hypothesis, as leptin-deficient mice have increased parturition times.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
King, M.-C., & Wilson, A. C. (1975) · Science · doi:10.1126/science.1090005 · Cited by 2,815 · see citing works
TRANSFAC(R) and its module TRANSCompel(R): transcriptional gene regulation in eukaryotes
Matys, V. (2005) · Nucleic Acids Research · doi:10.1093/nar/gkj143 · Cited by 2,142 · see citing works
Siglecs and their roles in the immune system
Crocker, P. R., Paulson, J. C., & Varki, A. P. (2007) · Nature reviews. Immunology · doi:10.1038/nri2056 · Cited by 2,032 · see citing works
Self-citationTRANSFAC(R): transcriptional regulation, from patterns to profiles
Matys, V. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg108 · Cited by 1,985 · see citing works
Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins
Varki, A. P. (2007) · Nature · doi:10.1038/nature05816 · Cited by 855 · see citing works
Self-citationInflammation in preterm and term labour and delivery
Romero, R. J., Espinoza, J., Gonçalves, L. F., Kusanovic, J. P., Friel, L. A., & Nien, J. K. (2006) · Seminars in Fetal and Neonatal Medicine · doi:10.1016/j.siny.2006.05.001 · Cited by 746 · see citing works
Siglecs—the major subfamily of I-type lectins
Varki, A. P., & Angata, T. (2005) · Glycobiology · doi:10.1093/glycob/cwj008 · Cited by 518 · see citing works
Self-citationThe natural history of human gait and posture. Part 1. Spine and pelvis.
Lovejoy, C. (2005) · Gait & Posture · doi:10.1016/j.gaitpost.2004.01.001 · Cited by 392 · see citing works
Chou, H.-H., Hayakawa, T., Diaz, S. L., Krings, M., Indriati, E., Leakey, M. G., Pääbo, S., Satta, Y., Takahata, N., & Varki, A. P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182257399 · Cited by 351 · see citing works
Self-citationVarki, A. P., & Diaz, S. L. (1984) · Analytical Biochemistry · doi:10.1016/0003-2697(84)90377-4 · Cited by 259 · see citing works
Self-citationThe Genomic Record of Humankind's Evolutionary Roots
Goodman, M. (1999) · The American Journal of Human Genetics · doi:10.1086/302218 · Cited by 247 · see citing works
Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia
Levine, R. J., Lam, C., Qian, C., Yu, K., Maynard, S. E., Sachs, B. P., Sibai, B. M., Epstein, F. H., Romero, R. J., Thadhani, R., et al. (2007) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000253489.32189.4d · Cited by 216 · see citing works
Loss of Siglec expression on T lymphocytes during human evolution
Nguyen, D. H., Hurtado-Ziola, N., Gagneux, P., & Varki, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510484103 · Cited by 204 · see citing works
Self-citationNormal Labor: Mechanism and Duration
Liao, J. B., Buhimschi, C. S., & Norwitz, E. R. (2005) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/j.ogc.2005.01.001 · Cited by 188 · see citing works
Identification of a Placental Enhancer for the Human Leptin Gene
Bi, S., Gavrilova, O., Gong, D.-W., Mason, M. M., & Reitman, M. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.48.30583 · Cited by 186 · see citing works
Steger, D. J., Hecht, J. H., & Mellon, P. L. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.8.5592 · Cited by 184 · see citing works
Patel, N., der Linden, E. C. M. B.-V., Altmann, S. W., Gish, K., Balasubramanian, S., Timans, J. C., Peterson, D., Bell, M. P., Bazán, J. F., Varki, A. P., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.32.22729 · Cited by 170 · see citing works
Self-citationder Linden, E. C. M. B.-V., & Varki, A. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8625 · Cited by 168 · see citing works
Self-citationAngata, T., Margulies, E. H., Green, E. D., & Varki, A. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404833101 · Cited by 165 · see citing works
Self-citationAbnormal placentation and the syndrome of preeclampsia
McMaster, M., Zhou, Y., & Fisher, S. J. (2004) · Seminars in Nephrology · doi:10.1016/s0270-9295(04)00124-x · Cited by 143 · see citing works
Mounzih, K., Qiu, J., Toland, A. E., & Chehab, F. F. (1998) · Endocrinology · doi:10.1210/endo.139.12.6523 · Cited by 141 · see citing works
A Human-Specific Gene in Microglia
Hayakawa, T., Angata, T., Lewis, A. L., Mikkelsen, T. S., Varki, N. M., & Varki, A. P. (2005) · Science · doi:10.1126/science.1114321 · Cited by 130 · see citing works
Self-citationFunctional Proteomics: Examining the Effects of Hypoxia on the Cytotrophoblast Protein Repertoire
Hoang, V. M., Foulk, R. A., Clauser, K. R., Burlingame, A. L., Gibson, B. W., & Fisher, S. J. (2001) · Biochemistry · doi:10.1021/bi0023910 · Cited by 115 · see citing works
Angata, T. (2002) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(02)00316-1 · Cited by 112 · see citing works
The Role of Leukocyte Traffic and Activation in Parturition
Yellon, S. M., Mackler, A. M., & Kirby, M. A. (2003) · Journal of the Society for Gynecologic Investigation · doi:10.1016/s1071-5576(03)00116-3 · Cited by 95 · see citing works
Comparative studies on the initiation of labor
Nathanielsz, P. W. (1998) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/s0301-2115(98)00058-x · Cited by 74 · see citing works
Overview of Current Research in Parturition
Bernal, A. L. (2001) · Experimental Physiology · doi:10.1113/eph8602178 · Cited by 67 · see citing works
Cell surface sialic acid influences tumor cell recognition in the mixed lymphocyte reaction.
Powell, L. D., Whiteheart, S. W., & Hart, G. W. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.139.1.262 · Cited by 63 · see citing works
Shi, D., Winston, J. H., Blackburn, M. R., Datta, S. K., Hanten, G. R., & Kellems, R. E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.4.2334 · Cited by 55 · see citing works
Takei, Y., Sasaki, S., Fujiwara, T., Takahashi, E., Muto, T., & Nakamura, Y. (2008) · Cytogenetics and Cell Genetics · doi:10.1159/000134676 · Cited by 52 · see citing works
Nuamah, M. A., Yura, S., Sagawa, N., et al. (2004) · Endocrine Journal · doi:10.1507/endocrj.51.177 · Cited by 49 · see citing works
Immunohistochemical assays in prostatic biopsies processed in Bouin’s fixative
Ananthanarayanan, V., Pins, M. R., Meyer, R. E., et al. (2005) · Journal of Clinical Pathology · doi:10.1136/jcp.2004.019299 · Cited by 39 · see citing works
Cook, J. L., & Karim, K. (2003) · doi:10.1002/9780470693896.ch13 · Cited by 33 · see citing works
Parturition in non-human primates: Pain and auditory concealment
Lefebvre, L., & Carli, G. (1985) · Pain · doi:10.1016/0304-3959(85)90161-7 · Cited by 22 · see citing works
Nonhuman primate models of toxemia of pregnancy.
Chez, R. A. (1976) · PubMed · Cited by 20 · see citing works
Cis-acting elements regulating the placenta-specific promoter of the bovine Cyp19 gene
Kalbe, C., Furbass, R., Schwerin, M., & Vanselow, J. (2000) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0250265 · Cited by 17 · see citing works
Functional Map of a Placenta-specific Enhancer of the Human Leukemia Inhibitory Factor Receptor Gene
Wang, Z., & Melmed, S. K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.40.26069 · Cited by 13 · see citing works
The onset of human labor: current theories
Navitsky, J., Greene, J. F., & Curry, S. (2000) · Primary Care Update for OB/GYNS · doi:10.1016/s1068-607x(00)00046-9 · Cited by 12 · see citing works
Hemispheric difference in human skin color
Chaplin, G., & Jablonski, N. G. (1998) · American Journal of Physical Anthropology · doi:10.1002/(sici)1096-8644(199810)107:2
Flagged first, then by citations
Cited by
Sorted by citations
Varki, A. (2017) · Glycobiology · doi:10.1093/glycob/cww086 · Cited by 2,635 · see citing works
“After fertilization, there is evidence that glycans and glycan-binding proteins are involved in the processes of implantation (944) and placental functions (945, 946) in mammals.”
BackgroundSelf-citationThe Evolution, Regulation, and Function of Placenta-Specific Genes
Rawn, S. M., & Cross, J. C. (2008) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.24.110707.175418 · Cited by 222 · see citing works
Evolution of genetic and genomic features unique to the human lineage
O'Bleness, M., Searles, V. B., Varki, A., Gagneux, P., & Sikela, J. M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3336 · Cited by 168 · see citing works
Self-citation
- Authors
- Brinkman-Van der Linden, E. C. M., Hurtado-Ziola, N., Hayakawa, T., Wiggleton, L., Benirschke, K., Varki, A., & Varki, N.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Varki, A.
- Venue
- Glycobiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-04-18
- Volume
- 17
- Issue
- 9
- Pages
- 922-931
- ISSN
- 0959-6658 (ISSN-L)
- 1460-2423
- OpenAlex
- W2164443274
- Cited by
- 123
- References
- 39
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 15 · 2022: 11 · 2021: 5 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 1 · 2012: 10
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Glycobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM032373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Keywords
- Siglec-6, placenta, trophoblast, human evolution, great apes, sialic acid, leptin, negative signaling, transcription factor binding sites, endometrium, childbirth, labor duration
- MeSH terms
- Animals, Antibodies, Monoclonal, Base Sequence, Pan troglodytes, Cytosol, Humans, Molecular Sequence Data, Placenta, Species Specificity, Transcription, Genetic, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Gene Expression Regulation, Developmental, N-Acetylneuraminic Acid, 5' Untranslated Regions, Lectins, Mice, Sialic Acid Binding Ig-like Lectin 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review