title: Role of Erk1/2 signaling in the regulation of neutrophil versus monocyte development in response to G-CSF and M-CSF.
abstract: Lineage specification in the hematopoietic system depends on the expression of lineage specific transcription factors. However, the role of hematopoietic cytokines in this process has been controversial and little is known about the intracellular signaling mechanisms by which cytokines instruct lineage choice. G-CSF and M-CSF are two lineage-specific cytokines that play a dominant role in granulopoiesis and monopoiesis, respectively. We show here that a G-CSFR mutant in which tyrosine 729 had been mutated to phenylalanine (Y729F) promoted monocyte rather than neutrophil development in myeloid precursors, which was associated with prolonged activation of Erk1/2 and augmented activation of downstream targets c-Fos and Egr1. Inhibition of Erk1/2 activation or knockdown of c-Fos or Egr1 largely rescued neutrophil development in cells expressing G-CSFR Y729F. We also show that M-CSF, but not G-CSF, stimulated strong and sustained activation of Erk1/2 in mouse lineage marker negative (Lin(-)) bone marrow cells. Significantly, inhibition of Erk1/2 signaling in these cells favored neutrophil over monocyte development in response to M-CSF. Thus, prolonged Erk1/2 activation resulted in monocyte development following G-CSF induction whereas inhibition of Erk1/2 signaling promoted neutrophil development at the expense of monocyte formation in response to M-CSF. These results reveal an important mechanism by which G-CSF and M-CSF instruct neutrophil versus monocyte lineage choice, i.e. differential activation of Erk1/2 pathway.
authors: From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors: Nan
authors: N
authors: Hu
authors: From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors: Yaling
authors: Y
authors: Qiu
authors: From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 fan.dong@utoledo.edu.
authors: Fan
authors: F
authors: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000201:enzymology*; D009154:Mutation; D038042:Myelopoiesis / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology*; D034622:RNA Interference; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
chemical_list: D016207:Cytokines; D016179:Granulocyte Colony-Stimulating Factor; D014443:Tyrosine; D016173:Macrophage Colony-Stimulating Factor
keywords: cell differentiation; cytokine action; hematopoiesis; lineage specification; monocyte; myeloid development; neutrophil; signaling; transcription factor