Kwon Kyongrim, Hutter Caroline, Sun Qiong, Bilic Ivan, Cobaleda César, Malin Stephen, Busslinger Meinrad
Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Immunity. 2008 Jun;28(6):751-62. doi: 10.1016/j.immuni.2008.04.014.
The transcription factor E2A controls the initiation of B lymphopoiesis, which is arrested at the pre-pro-B cell stage in E2A-deficient mice. Here, we demonstrate by conditional mutagenesis that E2A is essential for the development of pro-B, pre-B, and immature B cells in the bone marrow. E2A is, however, dispensable for the generation of mature B cells and plasma cells in peripheral lymphoid organs. In contrast, germinal center B cell development is impaired in the absence of E2A despite normal AID expression and class-switch recombination. Molecular analysis revealed that E2A is required not only for initiating but also for maintaining the expression of Ebf1, Pax5, and the B cell gene program in pro-B cells. Notably, precocious Pax5 transcription from the Ikzf1 locus promotes pro-B cell development in E2A-deficient mice, demonstrating that ectopic Pax5 expression is sufficient to activate the B lymphoid transcription program in vivo in the absence of E2A.
转录因子E2A控制B淋巴细胞生成的起始，在E2A缺陷型小鼠中，B淋巴细胞生成在pro-B前体细胞阶段停滞。在此，我们通过条件性诱变证明，E2A对于骨髓中pro-B细胞、前B细胞和未成熟B细胞的发育至关重要。然而，E2A对于外周淋巴器官中成熟B细胞和浆细胞的产生并非必需。相反，尽管AID表达正常且类别转换重组正常，但在缺乏E2A的情况下，生发中心B细胞的发育受损。分子分析表明，E2A不仅对于pro-B细胞中Ebf1、Pax5和B细胞基因程序的起始表达是必需的，而且对于其维持表达也是必需的。值得注意的是，来自Ikzf1基因座的早熟Pax5转录促进了E2A缺陷型小鼠中pro-B细胞的发育，这表明在缺乏E2A的情况下，异位Pax5表达足以在体内激活B淋巴细胞转录程序。
