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Molecular and Cellular Biology, August 2007, p. 5849-5859, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00802-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Agm1/Pgm3-Mediated Sugar Nucleotide Synthesis Is Essential for Hematopoiesis and Development{triangledown}

Kylie T. Greig,1,5,{dagger} Jennifer Antonchuk,2,{dagger} Donald Metcalf,2 Phillip O. Morgan,2 Danielle L. Krebs,2 Jian-Guo Zhang,2 Douglas F. Hacking,1 Lars Bode,6 Lorraine Robb,2 Christian Kranz,6 Carolyn de Graaf,1,5 Melanie Bahlo,3 Nicos A. Nicola,2 Stephen L. Nutt,4 Hudson H. Freeze,6 Warren S. Alexander,2 Douglas J. Hilton,1 and Benjamin T. Kile1,5*

Division of Molecular Medicine,1 Division of Cancer and Hematology,2 Division of Bioinformatics,3 Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia,4 Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia,5 Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 920376

Received 7 May 2007/ Accepted 24 May 2007

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.

* Corresponding author. Mailing address: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia. Phone: (61-3) 9345 2555. Fax: (61-3) 9347 0852. E-mail: kile{at}wehi.edu.au

{triangledown} Published ahead of print on 4 June 2007.

{dagger} The contributions of K.T.G. and J.A. should be considered equal.

Molecular and Cellular Biology, August 2007, p. 5849-5859, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00802-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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