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Abstract
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.
We thank Jason Corbin, Elizabeth Viney, Sandra Mifsud, Ladina Di Rago, Lynne Hartley, Katya Henley, and Adrienne Hilton for their expert technical assistance. We thank Toshiyuki Mio for generously providing reagents.
This work was supported by grants from the Australian National Health and Medical Research Council (program 257500), the National Cancer Institute (CA22556), the Cancer Council of Victoria, MuriGen Pty. Ltd., and the National Institutes of Heath (R01 DK55615 [H.H.F.]). B.T.K. is supported by a Queen Elizabeth II Fellowship from the Australian Research Council. K.T.G. is supported by a Stella Mary Langford Scholarship from the University of Melbourne. J.A. was supported by a postdoctoral fellowship from the Leukemia and Lymphoma Society. D.L.K. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research. L.B. and C.K. are supported by fellowships from the Deutsche Forschungsgemeinschaft (KR 2916/1-1 to C.K. and BO 2488/1-1 to L.B.).