The overall goal of this grant application is to support a K08 career development award that focuses on studying the role of the fucosylation-dependent Notch signaling pathway in the regulation of myeloid fate specification and myeloid lineage development. Fucosylated glycans are implicated in many bilogical processes. Fucosylation as O-linked fucose moieties on Notch extracellular EGF repeats is required for Notch signaling in various types of cell fate specification. Lan Zhou, the principle investigator of this proposal, in her previous work with Dr. John Lowe, and in her research conducted at Case Western Reserve University, identified a myeloproliferative phenotype in FX-/- mice, which are conditionally deficient in cellular fucosylation, is consequent to loss of Notch-dependent signal transduction on myeloid progenitor cells. In this proposal, Dr. Zhou will use a transgenic Notch reporter mouse to examine whether the marrrow hematopoietic stem and myeloid progenitor cells have suppressed Notch signal transduction as a consequence of fucosylation deficiency. She will then determine if fucosylation-deficient hematopoietic progenitor cells display altered interactions with the marrow stromal environment. She will further examine the role of O-fucosylation in modifying Notch signaling in granulopoiesis by using mice deficient in the expression of pofut! that mediates the fucosylation of Notch EGF repeats, and by studying the pofutl-/- ES cell in vitro hematopoiesis. Finally, she will examine specifically which O-fucose residue on Notch! EGF repeats is important for Notch to exert its effect in granulopoietic regulation. This will be the first study to define the signaling transduction pathways controlling myelopoiesis that are activated in bone marrow stem and progenitor cells after engagement of fucosylated glycoprotein, such as Notch, with bone marrow microenviroment, and the mechanisms that ultimately contribute to the regulation of granulopoiesis. The outcome of these studies will provide insights as to whether dysregulated Notch signaling consequent to deficiency of O-fucosylation could play a role in human chronic myeloproliferative diseases. Resutls from the proposal will provide the basis for future studies to explore the significance of fucosylated glycoproteins including Notch and Notch ligands, and, perhaps other secreted or membrane associated fucosylated glycans, in hematopoietic stem cell self-renewal, myeloid fate specification and determination, and bone marrow niche competency in supproting hematopoietic stem cell activity.
|Wang, Yiwei; Huang, Dan; Chen, Kai-Yuan et al. (2017) Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma. Gastroenterology 152:193-205.e10|
|Wang, Weihuan; Zimmerman, Grant; Huang, Xiaoran et al. (2016) Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function. Cancer Res 76:1641-52|
|Wang, Weihuan; Yu, Shuiliang; Zimmerman, Grant et al. (2015) Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention. Stem Cells 33:2280-93|
|Yao, David; Huang, Yuanshuai; Huang, Xiaoran et al. (2011) Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions. Blood 117:5652-62|
|Yan, Quanjian; Yao, David; Wei, Lebing L et al. (2010) O-fucose modulates Notch-controlled blood lineage commitment. Am J Pathol 176:2921-34|
|Myers, Jay; Huang, Yuanshuai; Wei, Lebing et al. (2010) Fucose-deficient hematopoietic stem cells have decreased self-renewal and aberrant marrow niche occupancy. Transfusion 50:2660-9|