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Unrestrained erythroblast development in Nix −/− mice reveals a mechanism for apoptotic modulation of erythropoiesis
- Source :
- Proceedings of the National Academy of Sciences. 104:6794-6799
- Publication Year :
- 2007
- Publisher :
- Proceedings of the National Academy of Sciences, 2007.
-
Abstract
- Normal production of RBCs requires that the antiapoptotic protein Bcl-xl be induced at end stages of differentiation in response to erythropoietin (Epo) signaling. The critical proapoptotic pathways inhibited by Bcl-xl in erythroblasts are unknown. We used gene targeting in the mouse to evaluate the BH3-only factor Nix, which is transcriptionally up-regulated during Epo-stimulated in vitro erythrocyte differentiation. Nix null mice are viable and fertile. Peripheral blood counts revealed a profound reticulocytosis and thrombocytosis despite normal serum Epo levels and blood oxygen tension. Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. Hematopoietic progenitor populations were unaffected. Cultured Nix null erythroid cells were hypersensitive to Epo and resistant to apoptosis stimulated by cytokine deprivation and calcium ionophore. Transcriptional profiling of Nix null spleens revealed increased expression of cell cycle and erythroid genes, including Bcl-xl, and diminished expression of cell death and B cell-related genes. Thus, cell-autonomous Nix-mediated apoptosis in opposition to the Epo-induced erythroblast survival pathway appears indispensable for regulation of erythrocyte production and maintenance of hematological homeostasis. These results suggest that physiological codependence and coordinated regulation of pro- and antiapoptotic Bcl2 family members may represent a general regulatory paradigm in hematopoiesis.
- Subjects :
- Programmed cell death
Erythroblasts
Cell Survival
Erythrocytes, Abnormal
Apoptosis
Mice, Transgenic
Mitochondria, Liver
Biology
Permeability
Mitochondrial Proteins
Mice
Erythroblast
hemic and lymphatic diseases
Erythrocyte differentiation
medicine
Animals
Erythropoiesis
Erythropoietin
Cells, Cultured
Mice, Knockout
Multidisciplinary
Membrane Proteins
Intracellular Membranes
Biological Sciences
Cell biology
Mice, Inbred C57BL
Haematopoiesis
Erythrocyte maturation
Signal transduction
Apoptosis Regulatory Proteins
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 104
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....cba1dec1c01811094491213decd3a2ac