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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1198-1207.
Prepublished online as a Blood First Edition Paper on April 20, 2006; DOI 10.1182/blood-2006-02-004184.
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Submitted February 16, 2006
Accepted March 25, 2006
Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development
Bogdan Dumitriu, Michael R Patrick, Jane P Petschek, Srujana Cherukuri, Ursula Klingmuller, Paul L Fox, and Veronique Lefebvre*
Department of Biomedical Engineering and Orthopaedic Research Center, Cleveland Clinic
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic
German Cancer Research Center
* Corresponding author; email: lefebvv{at}ccf.org.
Erythropoiesis, the essential process of hematopoietic stem cell development into erythrocytes, is controlled by lineage-specific transcription factors that determine cell fate and differentiation and by the hormone erythropoietin that stimulates cell survival and proliferation. Here, we identify the Sry-related HMG box transcription factor Sox6 as an important enhancer of definitive erythropoiesis. Sox6 is highly expressed in proerythroblasts and erythroblasts in the fetal liver, neonatal spleen, and bone marrow. Mouse fetuses and pups lacking Sox6 develop erythroid cells slowly and feature misshapen, short-lived erythrocytes. They compensate for anemia by elevating the serum level of erythropoietin and progressively enlarging their erythropoietic tissues. Erythroid-specific inactivation of Sox6 causes the same phenotype, demonstrating cell-autonomous roles for Sox6 in erythroid cells. Sox6 potentiates the ability of erythropoietin signaling to promote proerythroblast survival and has an effect additive to that of erythropoietin in stimulating proerythroblast and erythroblast proliferation. Sox6 also critically facilitates erythroblast and reticulocyte maturation, including hemoglobinization, cell condensation and enucleation, and ensures erythrocyte cytoskeleton long-term stability. It does not control adult globin and erythrocyte cytoskeleton genes, but acts by stabilizing F-actin levels. Sox6 thus enhances erythroid cell development at multiple levels and thereby ensures adequate production and quality of red blood cells.
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