Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision
Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision
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DOI：
10.1093/intimm/dxf030
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发表时间：
2002-06-01
影响因子：
4.4
通讯作者：
Honjo, T
中科院分区：
文献类型：
--
作者：
Han, H;Tanigaki, K;Honjo, T
转录因子重组信号结合蛋白-J（RBP-J）在细胞表面受体Notch的下游起作用，并通过所有四种Notch受体的胞内结构域介导转录激活。为了研究RBP-J的功能，我们在编码其DNA结合结构域的RBP-J外显子的两侧引入loxP位点。携带loxP侧翼RBP-J等位基因RBP-J（f/f）的小鼠与Mx-Cre转基因小鼠交配，并通过注射IFN-α诱导剂poly（I）-poly（C）诱导成年小鼠中RBP-J基因的缺失突变。在这里，我们表明，骨髓中RBP-J的失活导致T细胞发育在最早阶段的阻滞和胸腺中B细胞发育的增加。当通过悬滴胎儿胸腺器官培养在2 '-脱氧鸟苷处理的胎儿胸腺叶中培养时，RBP-J缺陷的类红细胞祖细胞分化为B细胞，而不是T细胞。竞争性再增殖试验也显示RBP-J基因敲除小鼠骨髓T细胞发育的细胞自主性缺陷。RBP-J灭活小鼠骨髓中的髓系和B谱系分化似乎正常。这些结果表明RBP-J可能通过介导Notch信号传导控制淋巴祖细胞中T细胞与B细胞的命运决定。
The transcription factor recombination signal binding protein-J (RBP-J) functions immediately downstream of the cell surface receptor Notch and mediates transcriptional activation by the intracellular domain of all four kinds of Notch receptors. To investigate the function of RBP-J, we introduced loxP sites on both sides of the RBP-J exons encoding its DNA binding domain. Mice bearing the loxP-flanked RBP-J alleles, RBP-J(f/f), were mated with Mx-Cre transgenic mice and deletional mutation of the RBP-J gene in adult mice was induced by injection of the IFN-alpha inducer poly(I)-poly(C). Here we show that inactivation of RBP-J in bone marrow resulted in a block of T cell development at the earliest stage and increase of B cell development in the thymus. Lymphoid progenitors deficient in RBP-J differentiate into B but not T cells when cultured in 2'-deoxyguanosine-treated fetal thymic lobes by hanging-drop fetal thymus organ culture. Competitive repopulation assay also revealed cell autonomous deficiency of T cell development from bone marrow of RBP-J knockout mouse. Myeloid and B lineage differentiation appears normal in the bone marrow of RBP-J-inactivated mice. These results suggest that RBP-J, probably by mediating Notch signaling, controls T versus B cell fate decision in lymphoid progenitors.