Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation.
Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation.
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DOI：
10.1182/blood-2007-08-104489
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发表时间：
2008-02
期刊：
影响因子：
20.3
通讯作者：
Daijiro Sugiyama;Makoto Tanaka;K. Kitajima;Jie Zheng;Hilo Yen;T. Murotani;A. Yamatodani;T. Nakano
中科院分区：
文献类型：
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作者：
Daijiro Sugiyama;Makoto Tanaka;K. Kitajima;Jie Zheng;Hilo Yen;T. Murotani;A. Yamatodani;T. Nakano
加塔-1的朋友（FOG-1）是加塔-1的结合伴侣，GATA-1是在红系、巨核细胞和肥大细胞分化中具有关键作用的锌指转录因子。FOG-1是加塔-1在巨核/巨核细胞生成过程中发挥作用所必需的，但FOG-1在肥大细胞中不表达。在这里，我们分析了FOG-1在肥大细胞分化中的作用，使用条件基因表达和小鼠胚胎干细胞体外造血诱导相结合的实验系统。FOG-1在祖细胞期的表达抑制肥大细胞的分化，促进中性粒细胞的分化。使用PU. 1突变体（一种与加塔-1正或负合作的转录因子）进行的分析显示，这种谱系偏斜是由加塔-1和PU. 1之间的破坏结合引起的，这是肥大细胞分化的先决条件。然而，FOG-1在成熟肥大细胞中的表达带来了大约可逆的肥大细胞表型损失。与谱系偏斜相反，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基本螺旋-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，并且其作用通过不同的分子机制产生。
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.