alpha(1,3)Fucosylated oligosaccharides represent components of leukocyte counterreceptors for E- and P-selectins and of L-selectin ligands expressed by lymph node high endothelial venules (HEV). The identity of the alpha(1,3)fucosyltransferase(s) required for their expression has been uncertain, as has a requirement for alpha(1,3)fucosylation in HEV L-selectin ligand activity. We demonstrate here that mice deficient in alpha(1,3) fucosyltransferase Fuc-TVII exhibit a leukocyte adhesion deficiency characterized by absent leukocyte E- and P-selectin ligand activity and deficient HEV L-selectin ligand activity. Selectin ligand deficiency is distinguished by blood leukocytosis, impaired leukocyte extravasation in inflammation, and faulty lymphocyte homing. These observations demonstrate an essential role for Fuc-TVII in E-, P-, and L-selectin ligand biosynthesis and imply that this locus can control leukocyte trafficking in health and disease.
E-, P-, and L-selectin counterreceptor activities, leukocyte trafficking, and lymphocyte homing are controlled prominently but incompletely by alpha(1,3)fucosyltransferase FucT-VII-dependent fucosylation. Molecular determinants for FucT-VII-independent leukocyte trafficking are not defined, and evidence for contributions by or requirements for other FucTs in leukocyte recruitment is contradictory and incomplete. We show here that inflammation-dependent leukocyte recruitment retained in FucT-VII deficiency is extinguished in FucT-IV(-/-)/FucT-VII(-/-) mice. Double deficiency yields an extreme leukocytosis characterized by decreased neutrophil turnover and increased neutrophil production. FucT-IV also contributes to HEV-born L-selectin ligands, since lymphocyte homing retained in FucT-VII(-/-) mice is revoked in FucT-IV(-/-)/FucT-VII(-/-) mice. These observations reveal essential FucT-IV-dependent contributions to E-, P-, and L-selectin ligand synthesis and to the control of leukocyte recruitment and lymphocyte homing.
The Gal␣133Gal structure is displayed on the zona pellucida glycoprotein ZP3 on murine oocytes. This trisaccharide has been implicated in sperm-zona pellucida adhesive events thought to be essential to fertilization in the mouse. To determine directly if this molecule is required for fertilization, we have generated mice that are deficient in a gene (␣1,3GT) encoding the UDPGal:-D-Gal-␣133Gal-galactosyltransferase enzyme responsible for Gal␣133Gal synthesis and expression. These mice develop normally and exhibit no gross phenotypic abnormalities. The Gal␣133Gal epitope is absent from the vascular endothelium and other tissues in ␣1,3GT (؊/؊) adult mice. By contrast, ␣1,3GT (؊/؊) mice, like humans, develop naturally occurring anti-␣-galactoside antibodies normally absent in wild type mice. Female ␣1,3GT (؊/؊) mice yield oocytes that are devoid of the Gal␣133Gal epitope; however, these mice are fully fertile. These observations indicate that the Gal␣133Gal moiety is not essential to sperm-oocyte interactions leading to fertilization or to essentially normal development. They further suggest that ␣1,3GT (؊/؊) mice will find utility for exploring approaches to diminish anti-Gal-dependent hyperacute xenograft rejection, which presents a major barrier to the use of porcine and other non-primate organs for xenotransplantation in humans.Fertilization in mammals involves an adhesive interaction between sperm and the zona pellucida, a glycoprotein-containing shell that surrounds the oocyte. Sperm receptor activity of the murine oocyte resides in the zona pellucida glycoprotein ZP3 (1). Sperm recognition of murine ZP3 depends upon Olinked oligosaccharides displayed by ZP3 (Ref. 2;. Treatment of purified egg ZP3 and ZP3-derived O-linked oligosaccharides with ␣-galactosidase eliminates sperm receptor activity (6). These observations have been taken to imply that terminal ␣-galactosides on ZP3 glycoconjugates are critical for sperm binding activity (6). This notion is supported by more recent observations demonstrating that structurally defined bi-and tetraantennary blood group I-related oligosaccharides containing terminal Gal␣133Gal moieties inhibit binding of sperm to eggs in a dose-dependent manner (7).In the mouse, at least one UDP-Gal:-D-Gal-␣133Gal-galactosyltransferase (␣1,3GT) 1 is responsible for the synthesis of terminal Gal␣133Gal134GlcNAc trisaccharides from common lactosamine-terminated glycoconjugates (8, 9). Mice and other placental mammals express the Gal␣133Gal134GlcNAc trisaccharide products of ␣1,3GT on a variety of glycoproteins and in a variety of tissues (10, 11). Aside from the postulated role of Gal␣133Gal moiety in murine fertilization, the function(s) of this structure are not known.By contrast, humans, apes, and Old World monkeys lack the ability to synthesize these oligosaccharide moieties, because the genetic homologues of the murine ␣1,3GT locus are pseudogenes incapable of encoding a functional ␣1,3GT (12, 13). Consequently, these latter species are reciprocally replete with immunoglobulins...
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