Functional analysis of transcription factors on development and defferentiation of hematopoietic cells

转录因子对造血细胞发育和分化的功能分析

• 批准号: 14370040
• 负责人: TAKAHASHI Satoru
• 金额: $ 7.62万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370040/
• 关键词: Hematopoiesis; Transcription Factors; Primitive Hematopoiesis; Maf transcription factors; GATA transcription factors; Endothelial cells; Mesoderm; f-Maf群転写因子; トランスジェニックマウス; ジーンターゲティング

We identified two things from this research projects. One is the function of DATA transcription factors in eosinophil development and the other is MafB function in Macrophage development1)The function of GATA transcription factors in eosinophil development. A high level of GATA-1 and GATA-expression has been observed in eosinophils, but their roles in eosinophil development remain uncertain both in vitro and in vivo. We showed that enforced expression of GATA-1 in human primary myeloid progenitor cells completely switches myeloid cell fate into eosinophils. Expression of GATA-1 exclusively promotes development and terminal maturation of eosinophils. GATA-1-deficient mice failed to develop eosinophil progenitors in the fetal-liver. On the other hand, DATA-2 also showed instructive capacity cumparable to GATA-1 in vitro and -efficiently compensated for GATA-1 deficiency in terms of eosinophil development in vivo, indicating that proper accumulation of GATA factors is critical for eosinophil development. Taken together, our findings establish essential and instructive roles of GATA factors in eosinophil development. GATA-1 and GATA-2 could be novel molecular targets for therapeutic approaches to allergic inflammation2)MafB function in Macrophage development. To investigate suspected MafB functions in hematopoiesis, the generates mafB/GFP knock-in null mutant mice. In hematopoietic cells, GFP expression was specifically observed in a subpopulation of granulocytes, myelomonocytes and differentiated macrophages, and eve identified that MafB was required for the development and normal function of a discrete subset of macrophages

我们从这个研究项目中发现了两件事。一是DATA转录因子在嗜酸性粒细胞发育中的作用，二是MafB在巨噬细胞发育中的作用1）加塔转录因子在嗜酸性粒细胞发育中的作用。在嗜酸性粒细胞中观察到高水平的加塔-1和GATA-1表达，但它们在体外和体内嗜酸性粒细胞发育中的作用仍不确定。我们发现，加塔-1在人原代髓系祖细胞中的强制表达完全将髓系细胞的命运转变为嗜酸性粒细胞。加塔-1的表达专门促进嗜酸性粒细胞的发育和终末成熟。加塔-1缺陷小鼠在胎肝中不能产生嗜酸性粒细胞祖细胞。另一方面，DATA-2还显示出在体外可与加塔-1互补的指导能力，并且在体内就嗜酸性粒细胞发育而言有效地补偿加塔-1缺陷，表明加塔因子的适当积累对于嗜酸性粒细胞发育是关键的。综上所述，我们的研究结果确立了加塔因子在嗜酸性粒细胞发育中的重要和指导性作用。加塔-1和加塔-2可能是治疗过敏性炎症的新分子靶点2）MafB在巨噬细胞发育中的功能。为了研究怀疑的MafB在造血中的功能，产生mafB/GFP敲入无效突变小鼠。在造血细胞中，在粒细胞、骨髓单核细胞和分化的巨噬细胞的亚群中特异性观察到GFP表达，并且已经确定MafB是巨噬细胞的离散亚群的发育和正常功能所必需的

项目成果

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