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Analysis of a tissue specific master regulator, PEBP2

组织特异性主调节因子 PEBP2 的分析

基本信息

批准号：
12309005
负责人：
ITO Yoshiaki
金额：
$ 29.89万
依托单位：
KYOTO UNIVRSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

There are three mammalian runt-related genes, Runxl/Amll,Runx2/Cbfal and Runx3/Pebp2αC. The function of Runx3 is poorly understood. To elucidate the function of Runx3, we generated mice that lack of the gene by homologuos recombination.1. In wild type mice, gastric epithelial cells express high levels of Runx3. When Runx3 was knocked out, the gastric mucosa exhibited hyperplasia and normal epithelial apoptosis was suppressed. This may be due to the reduced sensitivity of Runx3-/- epithelial cells to the growth-inhibiting and apoptosis-inducing activities of TGF- β.2. It was reported that Runx3 may be important in immunoglobulin (Ig) class switching from IgM to IgA because of its ability to activate the germline Ig C α promoter. It was seemed that Ig class switching might not be observed in Runx3-/- mice, however, in fact Ig class switching was observed in Runx3-/- mice as in WT mice. The possible involvement of the other Runx family genes in class switching is discussed.3. In the T-cell development, CD4+ or CD8+ single positive T cells develop from CD4+CD8+ double positive T cells. In a Runx3-deficient thymus, CD4+ single positive T cells develop normally but CD8+ single positive T cells do not. It is known that CD4 gene silencing play a role to establish CD8+ single positive T cells. These data demonstrated that Runx3 plays an essential role in CD4 gene silencing.4. Runx3-/- mice with the ICR background weredisplayed marked ataxia. trkC-expressing dorsal root ganglion neurons project their axons to specific target layers in the gray matter of the spinal cord, forming stretch-reflex circuit, however, it was found that proprioceptive afferent axons fail to reach the ventral horn in Runx3 is seemed to be essential for the axon pathfinding of trkC-expressing dorsal root ganglion neurons

哺乳动物中存在三个与侏儒相关的基因，Runx 1/Amll、Runx 2/Cbfal和Runx 3/Pebp 2 αC。Runx 3的功能知之甚少。为了阐明Runx 3的功能，我们通过同源重组产生了缺失该基因的小鼠.在野生型小鼠中，胃上皮细胞表达高水平的Runx 3。当Runx 3被敲除时，胃粘膜表现出增生，正常上皮细胞凋亡受到抑制。这可能是由于Runx 3-/-上皮细胞对TGF- β 2的生长抑制和凋亡诱导活性的敏感性降低。据报道Runx 3可能在免疫球蛋白（IG）类别从IgM转换为伊加中起重要作用，因为其能够激活生殖系IG C α启动子。似乎在Runx 3-/-小鼠中可能未观察到IG类别转换，然而，实际上在Runx 3-/-小鼠中观察到IG类别转换，与WT小鼠相同。讨论了其他Runx家族基因可能参与类别转换的情况。3.在T细胞发育中，CD 4+或CD 8+单阳性T细胞从CD 4 + CD 8+双阳性T细胞发育。在Runx 3缺陷的胸腺中，CD 4+单阳性T细胞正常发育，但CD 8+单阳性T细胞不正常。已知CD 4基因沉默在建立CD 8+单阳性T细胞中起作用。这些数据表明Runx 3在CD 4基因沉默中起重要作用.具有ICR背景的Runx 3-/-小鼠表现出明显的共济失调。表达trkC的背根神经节神经元将其轴突投射到脊髓灰质的特定靶层，形成牵张反射回路，然而，发现本体感受传入轴突未能到达Runx 3中的腹角，这似乎是表达trkC的背根神经节神经元轴突寻路所必需的