Agm1/Pgm3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development.
Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.
Greig
Kylie T
KT
Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
Antonchuk
Jennifer
J
Metcalf
Donald
D
Morgan
Phillip O
PO
Krebs
Danielle L
DL
Zhang
Jian-Guo
JG
Hacking
Douglas F
DF
Bode
Lars
L
Robb
Lorraine
L
Kranz
Christian
C
de Graaf
Carolyn
C
Bahlo
Melanie
M
Nicola
Nicos A
NA
Nutt
Stephen L
SL
Freeze
Hudson H
HH
Alexander
Warren S
WS
Hilton
Douglas J
DJ
Kile
Benjamin T
BT
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D047108:Embryonic Development; D005260:Female; D006031:Glycosylation; D006410:Hematopoiesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010179:Pancreas / Q000002:abnormalities; D010733:Phosphoglucomutase / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D012469:Salivary Glands / Q000002:abnormalities; D013091:Spermatogenesis; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000096:biosynthesis*
D014537:Uridine Diphosphate N-Acetylglucosamine; C522345:Pgm3 protein, mouse; D010733:Phosphoglucomutase