title: Loss of GADD34 induces early age-dependent deviation to the myeloid lineage.
abstract: Hematopoietic stem cells (HSCs) generate all known hematopoietic lineages and are capable of self-renewal. Upon aging, myeloid-biased HSCs are maintained, whereas lymphoid-biased HSCs are lost. GADD34 protein is expressed in myeloid-lineage cells and has been cloned from them. However, the function of GADD34 in the myeloid lineage has not yet been elucidated. Here, we show that early age-dependent deviation to the myeloid lineage occurs in GADD34-deficient mice. Early increases of GR-1(int)CD11b(+) and GR-1(high)CD11b(+) neutrophils were observed in the spleen, bone marrow (BM) and blood of GADD34-deficient mice. We found that BM Lin(-) c-Kit(+) Sca1(+) and Lin(-) c-Kit(+) Sca1(-)cells expressed GADD34 protein without stimulation and increased GADD34 expression following intravenous injection of Staphylococcus aureus (S.aureus). These cell populations were high in GADD34-deficient BM and were increased by the injection of S. aureus. Because of the increase in granulocyte colony-stimulating factor (G-CSF) induced by S. aureus injection, we examined the signaling pathway from the G-CSF receptor (G-CSFR). We found that phosphorylation of signal transducer and activator of transcription factor 3 was highly increased in GADD34-deficient Lin(-) BM cells by the stimulation of G-CSF. These results indicate that GADD34 binds to Lyn and inhibit G-CSFR signaling. We show here that GADD34 works to inhibit the proliferation and differentiation of HSCs or myeloid precursor cells and maintains homeostatic differentiation of neutrophil-lineage cells to avoid early immunological senescence.
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nishio
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Isobe
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000276:immunology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1