Agm1/Pgm3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development

Kylie T. Greig, Jennifer Antonchuk, Donald Metcalf, Phillip O. Morgan, Danielle L. Krebs, Jian Guo Zhang, Douglas F. Hacking, Lars Bode, Lorraine Robb, Christian Kranz, Carolyn De Graaf, Melanie Bahlo, Nicos A. Nicola, Stephen L. Nutt, Hudson H. Freeze, Warren S. Alexander, Douglas J. Hilton, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5849-5859
Number of pages11
JournalMolecular and Cellular Biology
Volume27
Issue number16
DOIs
Publication statusPublished - Aug 2007
Externally publishedYes

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