Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage.
Growth factor independence-1B (Gfi-1B) is a transcriptional repressor essential for erythropoiesis and megakaryopoiesis. Targeted gene disruption of GFI1B in mice leads to embryonic lethality resulting from failure to produce definitive erythrocytes, hindering the study of Gfi-1B function in adult hematopoiesis. We here show that, in humans, Gfi-1B controls the development of erythrocytes and megakaryocytes by regulating the proliferation and differentiation of bipotent erythro-megakaryocytic progenitors. We further identify in this cell population the type III transforming growth factor-beta receptor gene, TGFBR3, as a direct target of Gfi-1B. Knockdown of Gfi-1B results in altered transforming growth factor-beta (TGF-beta) signaling as shown by the increase in Smad2 phosphorylation and its inability to associate to the transcription intermediary factor 1-gamma (TIF1-gamma). Because the Smad2/TIF1-gamma complex is known to specifically regulate erythroid differentiation, we propose that, by repressing TGF-beta type III receptor (TbetaRIotaII) expression, Gfi-1B favors the Smad2/TIF1-gamma interaction downstream of TGF-beta signaling, allowing immature progenitors to differentiate toward the erythroid lineage.
Randrianarison-Huetz
Voahangy
V
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France.
Laurent
Benoit
B
Bardet
Valérie
V
Blobe
Gerard C
GC
Huetz
François
F
Duménil
Dominique
D
D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D034061:Thrombopoiesis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D009218:Myosins
D051017:Apoptosis Regulatory Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C111977:GFI1B protein, human; C497782:SMAD2 protein, human; C407152:MYO18A protein, human; D009218:Myosins; C071736:betaglycan