Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis
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Case Western Reserve University School of Graduate Studies / OhioLINK
2011
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1311379342 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case13113793422021-08-03T05:34:10Z Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis Yao, David C. Immunology fucose o-fucosyltransferase Notch Pofut1 myeloproliferation thymic hypoplasia hematopoiesis In mammals, fucose molecules are frequently present as a terminal modification of glycans. To elucidate the biological roles of fucose molecules, we previously characterized mice engineered to be conditionally deficient in all fucosylation. These mice yield phenotypes, including growth retardation, infertility, thymic hypoplasia and myeloproliferation. Functional analyses reveal that fucose-dependent thymic hypoplasia and myeloproliferation phenotypes are a result of defective Notch activity. Notch signaling is a conserved pathway that regulates cell fate determination. The extracellular domain of Notch is decorated with multiple O-fucose molecules, of which the additions are catalyzed by Protein O-fucosyltransferase-1 (Pofut1). These fucose-containing glycans have been demonstrated to be critical in modulating transactivation of Notch. To elucidate the role of O-fucose-dependent Notch activity in post-natal hematopoiesis, we studied mice with conditional inactivation of Pofut1. Adult animals bearing the homozygous Pofut1-deficient allele exhibits myeloproliferation, faulty marginal zone B-cell development and thymic hypoplasia in both cell-autonomous and non-autonomous fashions. Similarly, Pofut1-deficient bone marrow progenitors display robust myeloid development but fail to differentiate into T lymphocytes while co-culturing with Notch-ligand-expressing stromal cells in vitro. Both myeloproliferation and deficient mature T cell traits are reversed when Pofut1-deficient progenitors are reconstituted with constitutively active Notch1, which illustrates the critical role of Notch O-fucosylation in regulating hematopoietic homeostasis. Although O-glycans are essential for Notch function, it is unclear whether all O-fucose molecules are important. To address this issue, we used cell-based assays to assess the binding efficiency of the Notch ligands Delta-like-1, Delta-like-4, Jagged1 and Jagged2 to mouse Notch1 and the expression levels of surface Notch1 as a function of site-directed deletion of O-fucosylation sites thought to contribute to Notch biology (EGF domains 8, 9, 12, 24, 26 and 27). Binding and surface expression data from these studies are then correlated with Notch ligand-mediated signal transduction. These studies allow us to conclude that while multiple O-fucosylation sites modulate the surface expression of Notch1, O-fucose glycans in EGF9 and EGF12 play a primary role in regulating Delta-like-1, Delta-like-4 and Jagged2-mediated Notch binding and signaling. Together, our studies highlight the effects of multiple roles of O-fucose moieties on Notch activity and blood cell formation homeostasis. 2011 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1311379342 http://rave.ohiolink.edu/etdc/view?acc_num=case1311379342 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Immunology fucose o-fucosyltransferase Notch Pofut1 myeloproliferation thymic hypoplasia hematopoiesis |
| spellingShingle |
Immunology fucose o-fucosyltransferase Notch Pofut1 myeloproliferation thymic hypoplasia hematopoiesis Yao, David C. Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis |
| author |
Yao, David C. |
| author_facet |
Yao, David C. |
| author_sort |
Yao, David C. |
| title |
Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis |
| title_short |
Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis |
| title_full |
Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis |
| title_fullStr |
Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis |
| title_full_unstemmed |
Roles of O-fucose Molecules in Notch Signaling and Hematopoiesis |
| title_sort |
roles of o-fucose molecules in notch signaling and hematopoiesis |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2011 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1311379342 |
| work_keys_str_mv |
AT yaodavidc rolesofofucosemoleculesinnotchsignalingandhematopoiesis |
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1719421878765879296 |