Brinkman-Van der Linden Els C M, Hurtado-Ziola Nancy, Hayakawa Toshiyuki, Wiggleton Lisa, Benirschke Kurt, Varki Ajit, Varki Nissi
Glycobiology Research and Training Center, Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0687, USA.
Glycobiology. 2007 Sep;17(9):922-31. doi: 10.1093/glycob/cwm065. Epub 2007 Jun 18.
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.
CD33相关的唾液酸结合免疫球蛋白样凝集素（Siglecs）是免疫细胞上的凝集素，通过细胞外结构域识别唾液酸，并通过基于酪氨酸的胞质调节基序传递负信号。我们报告称，虽然Siglec-6/OB-BP1（也可结合瘦素）在人类和与之密切相关的大型猿类的免疫细胞上均有表达，但胎盘滋养层细胞的表达具有人类特异性，在猿类胎盘中几乎不表达或无表达。Siglec-6启动子区域中人类特异性转录因子识别位点的变化有助于解释这种人类特异性表达。人类胎盘在与Siglec-6表达相邻的区域也表达Siglec-6的天然配体（携带同源唾液酸化靶标的糖蛋白混合物）。在子宫内膜以及滋养层或子宫内膜来源的细胞系中也发现了配体。因此，在人类进化过程中，Siglec-6被募集到胎盘表达中，推测是为了与唾液酸化配体相互作用以实现特定的负信号功能和/或调节瘦素的可用性。人类分娩的控制机制尚不清楚，但涉及多种信号，包括胎盘信号。与我们最亲近的进化亲属大型猿类相比，人类分娩过程也更长。我们发现，在未知分娩史的择期手术分娩的胎盘中，Siglec-6水平通常较低，而在分娩结束后最高。因此，我们推测Siglec-6的负信号潜力被募集到人类特异性胎盘表达中，以减缓人类分娩过程的节奏。Siglec-6的瘦素结合能力也与这一假设一致，因为瘦素缺乏的小鼠分娩时间会延长。
