Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation.
Friend of GATA-1 (FOG-1) is a binding partner of GATA-1, a zinc finger transcription factor with crucial roles in erythroid, megakaryocytic, and mast-cell differentiation. FOG-1 is indispensable for the function of GATA-1 during erythro/megakaryopoiesis, but FOG-1 is not expressed in mast cells. Here, we analyzed the role of FOG-1 in mast-cell differentiation using a combined experimental system with conditional gene expression and in vitro hematopoietic induction of mouse embryonic stem cells. Expression of FOG-1 during the progenitor period inhibited the differentiation of mast cells and enhanced the differentiation of neutrophils. Analysis using a mutant of PU.1, a transcription factor that positively or negatively cooperates with GATA-1, revealed that this lineage skewing was caused by disrupted binding between GATA-1 and PU.1, which is a prerequisite for mast-cell differentiation. However, FOG-1 expression in mature mast cells brought approximately a reversible loss of the mast-cell phenotype. In contrast to the lineage skewing, the loss of the mast-cell phenotype was caused by down-regulation of MITF, a basic helix-loop-helix transcription factor required for mast-cell differentiation and maturation. These results indicate that FOG-1 inhibits mast-cell differentiation in a differentiation stage-dependent manner, and its effects are produced via different molecular mechanisms.
Department of Stem Cell Pathology, Medical School, Osaka University, Osaka, Japan.
Daijiro
D
Sugiyama
Makoto
M
Tanaka
Kenji
K
Kitajima
Jie
J
Zheng
Hilo
H
Yen
Tomotaka
T
Murotani
Atsushi
A
Yamatodani
Toru
T
Nakano
D002454:Cell Differentiation; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005434:Flow Cytometry; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008407:Mast Cells / Q000166:cytology* / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010957:Plasmids; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C498432:ZFPM1 protein, human