Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate
Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate
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DOI：
10.1073/pnas.0801074105
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发表时间：
2008-06-03
影响因子：
11.1
通讯作者：
Chiba, Shigeru
中科院分区：
文献类型：
--
作者：
Sakata-Yanagimoto, Mamiko;Nakagami-Yamaguchi, Etsuko;Chiba, Shigeru
肥大细胞被认为参与多种病理生理状况。然而，肥大细胞产生和成熟的调节机制仍有待阐明。肥大细胞发育过程可能受到细胞自主转录调节因子（例如 GATA 家族和 CCAAT/增强子结合蛋白 (C/EBP) 家族成员）的深刻影响。干细胞因子和 IL-3 等细胞外调节因子分别在基础细胞和诱导性肥大细胞生成中发挥重要作用。然而，细胞外信号传导和细胞转录控制之间的关系尚不清楚，肥大细胞发育的触发因素仍然难以捉摸。 Notch 信号在淋巴细胞生成中发挥着重要作用，但其在骨髓分化中的作用尚不清楚。在这里，我们证明Notch信号传导将环境线索和转录控制联系起来以决定肥大细胞的命运。 Delta 1 是一种已确定的 Notch 配体，根据 Notch2 基因的功能，指示骨髓共同髓系祖细胞和粒细胞-巨噬细胞祖细胞向肥大细胞谱系发展，但会牺牲其他粒细胞-巨噬细胞谱系。 Notch2信号传导导致Hes-1和GATA3上调，而这些转录因子的同时过度表达使祖细胞命运显着偏向含有肥大细胞的集落形成细胞。由于 Hes-1 过度表达，C/EBP α mRNA 在骨髓祖细胞中下调，这与最近提出的 C/EBP 下调对于肥大细胞命运决定所必需的提议一致。总而言之，Notch2 的信号传导通过协调上调 Hes-1 和 GATA3 来决定骨髓祖细胞向产生肥大细胞的祖细胞的命运。
Mast cells are thought to participate in a wide variety of pathophysiological conditions. Mechanisms of regulation, however, of mast cell production and maturation are still to be elucidated. Mast cell developmental process is likely to be profoundly affected by cell-autonomous transcriptional regulators such as the GATA family and CCAAT/enhancer binding protein (C/EBP) family members. Extracellular regulators such as stem cell factor and IL-3 have essential roles in basal and inducible mast cell generation, respectively. The relationship, however, between the extracellular signaling and cellular transcriptional control is unclear, and the trigger of the mast cell development remains elusive. Notch signaling plays a fundamental role in the lymphopoietic compartment, but its role in myeloid differentiation is less clear. Here, we demonstrate that Notch signaling connects environmental cues and transcriptional control for mast cell fate decision. Delta 1, an established Notch ligand, instructs bone marrow common myeloid progenitors and granulocyte-macrophage progenitors toward mast cell lineage at the expense of other granulocyte-macrophage lineages, depending on the function of the Notch2 gene. Notch2 signaling results in the up-regulation of Hes-1 and GATA3, whereas simultaneous overexpression of these transcription factors remarkably biases the progenitor fate toward the mast cell-containing colony-forming cells. C/EBP alpha mRNA was down-regulated in myeloid progenitors as a consequence of Hes-1 overexpression, in agreement with the recent proposal that the down-regulation of C/EBPa is necessary for mast cell fate determination. Taken together, signaling through Notch2 determines the fate of myeloid progenitors toward mast cell-producing progenitors, via coordinately up-regulating Hes-1 and GATA3.