title: ADAM17 limits the expression of CSF1R on murine hematopoietic progenitors.
abstract: All-lymphoid progenitors (ALPs) yield few myeloid cells in vivo, but readily generate such cells in vitro. The basis for this difference remains unknown. We hypothesized that ALPs limit responsiveness to in vivo concentrations of myeloid-promoting cytokines by reducing expression of the corresponding receptors, potentially through posttranscriptional mechanisms. Consistent with such a mechanism, ALPs express higher levels of CSF1R transcripts than their upstream precursors, yet show limited cell-surface protein expression of colony-stimulating factor 1 receptor (CSF1R). All-lymphoid progenitors and other hematopoietic progenitors deficient in A disintegrin and metalloproteinase domain 17 (ADAM17), display elevated cell surface CSF1R expression. ADAM17(-/-) ALPs, however, fail to yield myeloid cells upon transplantation into irradiated recipients. Moreover, ADAM17(-/-) ALPs yield fewer macrophages in vitro than control ALPs at high concentrations of macrophage colony stimulating factor. Mice with hematopoietic-specific deletion of ADAM17 have normal numbers of myeloid and lymphoid progenitors and mature cells in vivo. These data demonstrate that ADAM17 limits CSF1R protein expression on hematopoietic progenitors, but that compensatory mechanisms prevent elevated CSF1R levels from altering lymphoid progenitor potential.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Becker
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Walcheck
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States. Electronic address: deeptab@wustl.edu.
authors.forename: Deepta
authors.initials: D
authors.lastname: Bhattacharya
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism*; D038041:Lymphopoiesis / Q000187:drug effects / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse