Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development.
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 high-mobility-group (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 filamentous actin (F-actin) levels. Sox6 thus enhances erythroid cell development at multiple levels and thereby ensures adequate production and quality of red blood cells.
Dumitriu
Bogdan
B
Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH 44195, USA.
Patrick
Michael R
MR
Petschek
Jane P
JP
Cherukuri
Srujana
S
Klingmuller
Ursula
U
Fox
Paul L
PL
Lefebvre
Véronique
V
D000199:Actins / Q000096:biosynthesis; D000740:Anemia / Q000097:blood / Q000235:genetics / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D004900:Erythroblasts / Q000473:pathology / Q000502:physiology*; D004920:Erythropoiesis / Q000235:genetics; D004921:Erythropoietin / Q000097:blood; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D005914:Globins / Q000096:biosynthesis; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D012156:Reticulocytes / Q000378:metabolism / Q000473:pathology; D055755:SOXD Transcription Factors; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*
D000199:Actins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D014157:Transcription Factors; D004921:Erythropoietin; D005914:Globins