Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice
Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice
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DOI：
10.1073/pnas.94.2.569
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发表时间：
1997-01-21
影响因子：
11.1
通讯作者：
Tenen, DG
中科院分区：
文献类型：
--
作者：
Zhang, DE;Zhang, P;Tenen, DG
转录因子是分化的主要调节开关，包括从干细胞发育成特定的造血系。在这里，我们显示了靶向阻断CCAAT增强子结合蛋白α基因(C/EBPα)的小鼠表现出对中性粒细胞分化的选择性阻断。在突变动物的血液或胎肝中没有观察到成熟的中性粒细胞和嗜酸性粒细胞，而包括单核细胞在内的其他造血系也没有受到影响。相反，突变小鼠外周血中的大多数白细胞都有髓系母细胞的出现，我们还观察到粒细胞集落刺激因子受体CCAAT增强子结合蛋白α的关键基因靶标选择性缺失。因此，来自突变胎肝的多潜能髓系祖细胞不能对粒细胞集落刺激因子信号做出反应，尽管它们能够在其他生长因子的作用下在甲基纤维素中形成粒细胞-巨噬细胞集落，最后，我们证明粒细胞发育的缺乏是由于造血系统固有的缺陷所致；从突变小鼠移植的胎肝可以重建受者的淋巴样细胞，但不能重建中性粒细胞，这些研究提出了一种模型，在该模型中，转录因子可以通过激活特定的生长因子受体的表达来指导多潜能前体细胞的分化，允许对特定的细胞外信号做出反应的增殖和分化，此外，c/eBPα(-/-)小鼠可能有助于理解急性髓系白血病的发病机制，在急性髓系白血病中，髓系前体细胞的分化受阻是该疾病的关键特征。
Transcription factors are master regulatory switches of differentiation, including the development of specific hematopoietic lineages from stem cells. Here we show that mice with targeted disruption of the CCAAT enhancer binding protein alpha gene (C/EBP alpha) demonstrate a selective block in differentiation of neutrophils. Mature neutrophils and eosinophils are not observed in the blood or fetal liver of mutant animals, while other hematopoietic lineages, including monocytes, are not affected. Instead, most of the white cells in the peripheral blood of mutant mice had the appearance of myeloid blasts, We also observed a selective loss of expression of a critical gene target of CCAAT enhancer binding protein alpha, the granulocyte colony-stimulating factor receptor. As a result, multipotential myeloid progenitors from the mutant fetal liver are unable to respond to granulocyte colony-stimulating factor signaling, although they are capable of forming granulocyte-macrophage and macrophage colonies in methylcellulose in response to other growth factors, Finally, we demonstrate that the lack of granulocyte development results from a defect intrinsic to the hematopoietic system; transplanted fetal liver from mutant mice can reconstitute lymphoid hut not neutrophilic cells in irradiated recipients, These studies suggest a model by which transcription factors can direct the differentiation of multipotential precursors through activation of expression of a specific growth factor receptor, allowing proliferation and differentiation in response to a specific extracellular signal, In addition, the c/ebp alpha(-/-) mice may be useful in understanding the mechanisms involved in acute myelogenous leukemia, in which a block in differentiation of myeloid precursors is a key feature of the disease.