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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1924-1932.
Prepublished online as a Blood First Edition Paper on December 6, 2007; DOI 10.1182/blood-2007-08-104489.


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HEMATOPOIESIS

Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation

Daijiro Sugiyama1, Makoto Tanaka1, Kenji Kitajima1, Jie Zheng1, Hilo Yen1, Tomotaka Murotani2, Atsushi Yamatodani2, and Toru Nakano1

1 Department of Stem Cell Pathology, Medical School, and Graduate School of Frontier Biosciences and 2 Department of Medical Physics and Engineering, Division of Health Sciences, Graduate School of Medicine, Osaka University, Japan

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.


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