Disease relevance of Fut4

• To determine how the alpha(1,3)fucosyltransferases Fuc-TIV and Fuc-TVII, and the selectin ligands they control may contribute to the adaptive immune response, contact hypersensitivity (CHS) was characterized in mice deficient in either or both enzymes [1].
• These studies identify an important role for FucT-VII in atherogenesis, and a subsidiary role for FucT-IV, and implicate leukocyte selectin counter-receptors in the pathogenesis of atherosclerosis [2].
• Our observations indicate that leukocyte recruitment functions dictated by FucT-IV and FucT-VII-dependent selectin ligand activities are not critical for inducing or maintaining T cell effector responses at levels necessary to control pulmonary tuberculosis [3].
• For example, in order to monitor in vitro differentiation of multipotential embryonal carcinoma cells, stage-specific embryonic antigen-1 (SSEA-1) and the Lotus agglutinin receptor have been used as markers of the undifferentiated cells, and the Dolichos agglutinin receptor has been used as a marker of extraembryonic endoderm cells [4].
• During differentiation of human teratocarcinoma 2102Ep cells, the globo-series glycolipids defined by these antibodies decrease and the lacto-series glycolipids, reacting with the SSEA-1 antibody appear [5].

High impact information on Fut4

• Regulatory mutations in CHO cells induce expression of the mouse embryonic antigen SSEA-1 [6].
• The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing [7].
• 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 [7].
• These results demonstrate a role for FucT-IV in selectin-dependent adhesion and suggest that the endothelial selectins and FucTs have distinct but overlapping functions in the immunosurveillance of the skin [8].
• Throughout the culture period most cells within the colonies continued to be alkaline phosphatase-positive and tested positive against a panel of five immunological markers (SSEA-1, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81) that have been used routinely to characterize embryonic stem and EG cells [9].

Chemical compound and disease context of Fut4

• Murine embryonal carcinoma cell-surface sialyl LeX is present on a novel glycoprotein and on high-molecular-weight lactosaminoglycan [10].
• Methotrexate (MTX) was coupled to an IgM monoclonal antibody specific for stage-specific embryonic antigen-1 (SSEA-1), and the resulting immunoconjugate (MTX-anti-SSEA-1) was used for in vivo drug targeting in mice bearing MH-15 teratocarcinoma [11].
• Roles of cell surface carbohydrates containing the 3-fucosyl-N-acetyllactosamine and poly-N-acetyllactosamine sequences (SSEA-1 and I antigens, respectively) in the compaction of mouse embryos have been investigated using the endo-beta-galactosidase of Bacteroides fragilis to modify the surface of cleavage-stage embryos [12].

Biological context of Fut4

• Therefore, we conclude that expression of the SSEA-1 epitope in the developing mouse embryo is not essential for embryogenesis in vivo [13].
• For many years, SSEA-1 has been implicated in the development of mouse embryos as a functional carbohydrate epitope in cell-to-cell interaction during morula compaction [13].
• A comparison of gene expression profiles in PECAM1-positive cells that were either positive or negative for SSEA-1 expression identified only 53 genes that showed a more than 2-fold greater difference in expression levels between these subpopulations [14].
• METHODS AND RESULTS: Atherosclerotic lesion size and histology were determined in apolipoprotein E-/- mice sufficient or deficient in FucT-IV or FucT-VII [2].
• The knockdown of Oct4 but not beta2-microglobulin expression in both EC and ES cells resulted in their differentiation, as indicated by a marked change in morphology, growth rate, and surface antigen phenotype, with respect to SSEA1, SSEA3, and TRA-1-60 expression [15].

Anatomical context of Fut4

• The Fut9 transcript was detected in embryonic-day-13.5 gonads containing primordial germ cells, but the Fut4 transcript was not [13].
• Neurons and astrocytes in primary culture also expressed 10-15 times more Fut9 than Fut4 transcript [16].
• Furthermore, both cerebrum and cerebellum at various stages of development (E17, P0, P7, P30, P100) expressed 15-100 times more Fut9 transcript than Fut4 transcript [16].
• Moreover, alpha1,3-Fut activity toward a polylactosamine chain in homogenates of brain tissues and primary cultured cells showed a pattern typical of Fut9, not Fut4 [16].
• Stage-specific embryonic antigen 1 (SSEA-1), an antigenic epitope defined as a Lewis x carbohydrate structure, is expressed during the 8-cell to blastocyst stages in mouse embryos and in primordial germ cells, undifferentiated embryonic stem cells, and embryonic carcinoma cells [13].

Associations of Fut4 with chemical compounds

• Selectin ligand expression increased postischemia in wild-type, but not FucT-IV/FucT-VII-deficient, mice [17].
• The alpha (1,3)-fucosyltransferase Fuc-TIV, but not Fuc-TVII, generates sialyl Lewis X-like epitopes preferentially on glycolipids [18].
• In the case of mouse Fuc-TIV (mFuc-TIV) gene, its transcript was only detectable in RA-induced aggregates and not found in either undifferentiated or RA-induced neural cells [19].
• Moreover, PTPzeta-B did not contain LeX, HNK-1 carbohydrate, or keratan sulfate, although PTPzeta-A and -S were generally modified with these carbohydrates [20].
• Sialyl LeX was further shown to be carried by a novel glycoprotein, termed small lactosaminoglycan-like glycoprotein (sLAG) which could be purified by immunoaffinity chromatography [10].

Physical interactions of Fut4

• We show here that LeX-containing molecules in the developing nervous system bind Wnt-1 [21].

Regulatory relationships of Fut4

• Intravital microscopy experiments revealed that MECA-79-reactive ligands depend primarily on FucT-VII, whereas MECA-79-independent medullary L-selectin ligands are regulated by FucT-IV [22].
• In contrast, GFAP-expressing cells in similar cultures prepared from adult cerebral cortex did not express detectable levels of LeX/CD15, and exhibited no neurogenic potential [23].
• FACS analysis showed that the cells strongly positive for SSEA-1 co-expressed Ki67 proliferation antigen in all the developmental stages examined [24].
• In ovariectomized female mice treated with estrogen, SSEA-1 was the only antigen expressed at the uterine epithelium [25].

Other interactions of Fut4

• LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1 [21].
• Bilateral 30-min renal IRI was performed, and the results demonstrated that mice deficient in both FucT-IV/FucT-VII were significantly protected from renal IRI at 24 and 48 h compared with wild-type control mice [17].
• At the blastocyst stage, PECAM-1+ SSEA-1+/- cells were found to have differentiated into epiblast cells in high numbers [26].
• We found that LeX expression is particularly strong in neural regions with prolonged neurogenesis, e.g., the olfactory epithelium, hippocampus, basal forebrain and cerebellum [21].
• LeX/SSEA1/CD15 is an extracellular matrix-associated carbohydrate expressed by ES cells and by adult neural and bone marrow stem cells [21].

Analytical, diagnostic and therapeutic context of Fut4

• Using genomic PCR and reverse-transcriptase (RT)-PCR strategies, we isolated coding portions of the CHO Fut4 and Fut9 genes [27].
• Parental CHO cells and the revertants, LEC11.R9 and LEC12.R10, do not express this antigen as detected by a sensitive radioimmunoassay with a monoclonal antibody to SSEA-1 [6].
• Multiple labeling immunohistochemistry revealed that both primary astrocyte cultures and adherent neurogenic cultures derived from postnatal or adult periventricular tissue contained subpopulations of GFAP-expressing cells that co-expressed nestin and LeX/CD15, two molecules associated with NSCs [23].
• The identification of two cell surface markers, SSEA-1 and GM1, on both the native embryonic RG cells and ES-RG cells, may facilitate purification of radial glial cells for future studies and cell therapy [28].
• Fluorescence-activated cell sorting (FACS) of both primary astrocyte cultures and adherent neurogenic cultures for LeX/CD15 showed that GFAP-expressing cells competent to act as multipotent NSCs were concentrated in the LeX-positive fraction [23].

References