Targeted disruption of the gene encoding core 1 beta1-3-galactosyltransferase (T-synthase) causes embryonic lethality and defective angiogenesis in mice.
The biosynthesis of the core 1 O-glycan (Galbeta1-3GalNAcalpha1-Ser/Thr, T antigen) is controlled by core 1 beta1-3-galactosyltransferase (T-synthase), which catalyzes the addition of Gal to GalNAcalpha1-Ser/Thr (Tn antigen). The T antigen is a precursor for extended and branched O-glycans of largely unknown function. We found that wild-type mice expressed the sialyl-T antigen (NeuAcalpha2-3Galbeta1-3GalNAcalpha1-Ser/Thr) primarily in endothelial, hematopoietic, and epithelial cells during development. Gene-targeted mice lacking T-synthase instead expressed the nonsialylated Tn antigen in these cells and developed brain hemorrhage that was uniformly fatal by embryonic day 14. T-synthase-deficient brains formed a chaotic microvascular network with distorted capillary lumens and defective association of endothelial cells with pericytes and extracellular matrix. These data reveal an unexpected requirement for core 1-derived O-glycans during angiogenesis.
Xia
Lijun
L
Oklahoma Medical Research Foundation, Oklahoma City, USA.
McEver
Rodger P
RP
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis; D001921:Brain / Q000002:abnormalities* / Q000098:blood supply* / Q000473:pathology; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000473:pathology*; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics; D018390:Gene Targeting; D007150:Immunohistochemistry; D020300:Intracranial Hemorrhages / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics*
D015295:Antigens, Tumor-Associated, Carbohydrate; C040286:Tn antigen; C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases