title: Related-to-receptor tyrosine kinase receptor regulates hematopoietic stem and progenitor sensitivity to myelosuppressive injury in mice.
abstract: Maintaining a careful balance between quiescence and proliferation of hematopoietic stem and progenitor cells (HSPCs) is necessary for lifelong blood formation. Previously, we demonstrated that the Wnt5a ligand inhibits HSPC proliferation through a functional interaction with a noncanonical Wnt ligand receptor termed 'related-to-receptor tyrosine kinase' (Ryk). Expression of Ryk on HSPCs in vivo is associated with a lower rate of proliferation, and, following treatment with fluorouracil (5-FU), the percentage of Ryk(+/high) HSPCs increased and the percentage of Ryk(-/low) HSPCs decreased. Based on these data, we hypothesized that one function of the Ryk receptor is to protect HSPCs from the effects of myeloablative agents. We found that Ryk expression on HSPCs is associated with lower rates of apoptosis following 5-FU and radiation. Transient inhibition of Ryk signaling in vivo resulted in increased hematopoietic-stem-cell proliferation and decreased hematopoietic-stem-cell function in bone marrow transplant assays. Furthermore, inhibition of Ryk signaling sensitized HSPCs to 5-FU treatment in association with increased levels of reactive oxygen species. Together, these results demonstrated an association between Ryk expression and survival of HSPCs following suppressive injury.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Povinelli
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, United States.
authors.forename: Pragya
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, United States; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, United States. Electronic address: michael.nemeth@roswellpark.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nemeth
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse; D005472:Fluorouracil