Defective angiogenesis and fatal embryonic hemorrhage in mice lacking core 1-derived O-glycans.
The core 1 beta1-3-galactosyltransferase (T-synthase) transfers Gal from UDP-Gal to GalNAcalpha1-Ser/Thr (Tn antigen) to form the core 1 O-glycan Galbeta1-3GalNAcalpha1-Ser/Thr (T 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 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
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104, USA. lijun-xia@omrf.ouhsc.edu
Ju
Tongzhong
T
Westmuckett
Andrew
A
An
Guangyu
G
Ivanciu
Lacramioara
L
McDaniel
J Michael
JM
Lupu
Florea
F
Cummings
Richard D
RD
McEver
Rodger P
RP
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000235:genetics / Q000378:metabolism; D000957:Antigens, Viral, Tumor / Q000737:chemistry / Q000378:metabolism*; D001777:Blood Coagulation / Q000502:physiology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000473:pathology* / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D005865:Gestational Age; D006031:Glycosylation; D006470:Hemorrhage; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000033:anatomy & histology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D020286:Pericytes / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D011247:Pregnancy; D014018:Tissue Distribution
D015295:Antigens, Tumor-Associated, Carbohydrate; D000957:Antigens, Viral, Tumor; D011134:Polysaccharides; C040286:Tn antigen; D005700:Galactosyltransferases