title: Growth factor independence 1b (gfi1b) is important for the maturation of erythroid cells and the regulation of embryonic globin expression.
abstract: Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis. Gfi1b-null embryos die at midgestation very likely due to defects in erythro- and megakaryopoiesis. To analyze the full functionality of Gfi1b, we used conditionally deficient mice that harbor floxed Gfi1b alleles and inducible (Mx-Cre, Cre-ERT) or erythroid specific (EpoR-Cre) Cre expressing transgenes. In contrast to the germline knockout, EpoR-Cre mediated erythroid specific ablation of Gfi1b allows full gestation, but causes perinatal lethality with very few mice surviving to adulthood. Both the embryonic deletion of Gfi1b by EpoR-Cre and the deletion in adult mice by Mx-Cre or Cre-ERT leads to reduced numbers of erythroid precursors, perturbed and delayed erythroid maturation, anemia and extramedullary erythropoiesis. Global expression analyses showed that the Hba-x, Hbb-bh1 and Hbb-y embryonic globin genes were upregulated in Gfi1b deficient TER119+ fetal liver cells over the gestation period from day 12.5-17.5 p.c. and an increased level of Hbb-bh1 and Hbb-y embryonic globin gene expression was even maintained in adult Gfi1b deficient mice. While the expression of Bcl11a, a regulator of embryonic globin expression was not affected by Gfi1b deficiency, the expression of Gata1 was reduced and the expression of Sox6, also involved in globin switch, was almost entirely lost when Gfi1b was absent. These findings establish Gfi1b as a regulator of embryonic globin expression and embryonic and adult erythroid maturation.
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, Montréal, Québec, Canada.
authors.forename: Lothar
authors.initials: L
authors.lastname: Vassen
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, Montréal, Québec, Canada.
authors.forename: Hugues
authors.initials: H
authors.lastname: Beauchemin
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, Montréal, Québec, Canada.
authors.forename: Wafaa
authors.initials: W
authors.lastname: Lemsaddek
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, Montréal, Québec, Canada; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Krongold
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, Montréal, Québec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, Montréal, Québec, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada; Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism*; D004920:Erythropoiesis; D050982:GATA1 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D005914:Globins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055755:SOXD Transcription Factors / Q000378:metabolism
chemical_list: C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050982:GATA1 Transcription Factor; C486395:Gfi1b protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D005914:Globins