Medical Biology - Research Publications

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Author: Alexander, Warren × End date: 2009 × Start date: 2000 ×

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    Agm1/Pgm-3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development
    Greig, KT ; Antonchuk, J ; Metcalf, D ; Morgan, PO ; Krebs, DL ; Zhang, J-G ; Hacking, DF ; Bode, L ; Robb, L ; Kranz, C ; de Graaf, C ; Bahlo, M ; Nicola, NA ; Nutt, SL ; Freeze, HH ; Alexander, WS ; Hilton, DJ ; Kile, BT (AMER SOC MICROBIOLOGY, 2007-08)
    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.
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    Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity
    Majewski, IJ ; Blewitt, ME ; de Graaf, CA ; McManus, EJ ; Bahlo, M ; Hilton, AA ; Hyland, CD ; Smyth, GK ; Corbin, JE ; Metcalf, D ; Alexander, WS ; Hilton, DJ ; Goodell, MA (PUBLIC LIBRARY SCIENCE, 2008-04)
    Polycomb group proteins are transcriptional repressors that play a central role in the establishment and maintenance of gene expression patterns during development. Using mice with an N-ethyl-N-nitrosourea (ENU)-induced mutation in Suppressor of Zeste 12 (Suz12), a core component of Polycomb Repressive Complex 2 (PRC2), we show here that loss of Suz12 function enhances hematopoietic stem cell (HSC) activity. In addition to these effects on a wild-type genetic background, mutations in Suz12 are sufficient to ameliorate the stem cell defect and thrombocytopenia present in mice that lack the thrombopoietin receptor (c-Mpl). To investigate the molecular targets of the PRC2 complex in the HSC compartment, we examined changes in global patterns of gene expression in cells deficient in Suz12. We identified a distinct set of genes that are regulated by Suz12 in hematopoietic cells, including eight genes that appear to be highly responsive to PRC2 function within this compartment. These data suggest that PRC2 is required to maintain a specific gene expression pattern in hematopoiesis that is indispensable to normal stem cell function.