Sugiyama Daijiro, Tanaka Makoto, Kitajima Kenji, Zheng Jie, Yen Hilo, Murotani Tomotaka, Yamatodani Atsushi, Nakano Toru
Department of Stem Cell Pathology, Medical School, Osaka University, Osaka, Japan.
Blood. 2008 Feb 15;111(4):1924-32. doi: 10.1182/blood-2007-08-104489. Epub 2007 Dec 6.
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.
GATA-1的伙伴因子（FOG-1）是GATA-1的结合伴侣，GATA-1是一种锌指转录因子，在红细胞、巨核细胞和肥大细胞分化中起关键作用。在红细胞/巨核细胞生成过程中，FOG-1对于GATA-1的功能不可或缺，但肥大细胞中不表达FOG-1。在此，我们使用条件基因表达和小鼠胚胎干细胞体外造血诱导的联合实验系统，分析了FOG-1在肥大细胞分化中的作用。祖细胞期FOG-1的表达抑制了肥大细胞的分化，并增强了中性粒细胞的分化。使用与GATA-1正向或负向协同作用的转录因子PU.1的突变体进行分析，结果显示这种谱系偏向是由GATA-1与PU.1之间的结合破坏所致，而这是肥大细胞分化的前提条件。然而，成熟肥大细胞中FOG-1的表达使肥大细胞表型出现了近乎可逆的丧失。与谱系偏向相反，肥大细胞表型的丧失是由MITF的下调引起的，MITF是肥大细胞分化和成熟所需的一种碱性螺旋-环-螺旋转录因子。这些结果表明，FOG-1以分化阶段依赖性方式抑制肥大细胞分化，且其作用是通过不同的分子机制产生的。
