Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts.
Erythropoietin (Epo) controls red cell production in the basal state and during stress. Epo binding to its receptor, EpoR, on erythroid progenitors leads to rapid activation of the transcription factor Stat5. Previously, fetal anemia and increased apoptosis of fetal liver erythroid progenitors were found in Stat5a(-/-)5b(-/-) mice. However, the role of Stat5 in adult erythropoiesis was not clear. The present study shows that some adult Stat5a(-/-)5b(-/-) mice have a near-normal hematocrit but are deficient in generating high erythropoietic rates in response to stress. Further, many adult Stat5a(-/-)5b(-/-) mice have persistent anemia despite a marked compensatory expansion in their erythropoietic tissue. Analysis of erythroblast maturation in Stat5a(-/-)5b(-/-) hematopoietic tissue shows a dramatic increase in early erythroblast numbers, but these fail to progress in differentiation. Decreased expression of bcl-x(L) and increased apoptosis in Stat5a(-/-)5b(-/-) early erythroblasts correlate with the degree of anemia. Hence, Stat5 controls a rate-determining step regulating early erythroblast survival.
Socolovsky
M
M
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Nam
H
H
Fleming
M D
MD
Haase
V H
VH
Brugnara
C
C
Lodish
H F
HF
D000740:Anemia / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004900:Erythroblasts / Q000737:chemistry / Q000473:pathology; D004906:Erythrocyte Count; D015672:Erythroid Precursor Cells / Q000473:pathology; D004920:Erythropoiesis / Q000235:genetics*; D004921:Erythropoietin / Q000502:physiology; D005315:Fetal Diseases / Q000235:genetics; D005838:Genotype; D006400:Hematocrit; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D017467:Receptors, Erythropoietin / Q000502:physiology; D050799:STAT5 Transcription Factor; D013154:Spleen / Q000737:chemistry / Q000473:pathology; D013312:Stress, Physiological / Q000503:physiopathology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D051020:bcl-X Protein; D004921:Erythropoietin