Signal Regulation Mechanisms for B Cell Development and Self-Tolerance Establishment.

前B细胞受体（pre-B cell receptor，pre-BCR）信号转导可诱导大的前B细胞增殖扩增并分化为小的前B细胞（pre-B cell transition，前B细胞转化），抑制IgH基因座的VH重排（IgH allelic exclusion，IgH等位基因排斥），后者也可解释表达Dμ蛋白的前B细胞的反选择（Dμ selection，Dμ选择）。我们以前已经表明，B细胞特异性衔接蛋白BASH（或BLNK/SLP-65），这是B细胞抗原受体（BCR）信号传导的关键，是重要的，但不是必不可少的，前B细胞过渡。在这项研究中，我们发现了CD 19在BCR前信号传导中的作用，CD 19是BCR的B细胞特异性共受体。在BASH/CD 19双突变小鼠中，前B细胞转化完全消除，大的非循环、前BCR表达细胞的积累增加。然而，即使在双突变小鼠中，IgH等位基因排斥也是完整的，而Dμ选择在BASH和双突变小鼠中被消除。因此， ...更多信息 这些事件需要清晰的信号。此外，这些小鼠死于前B细胞白血病，表明BASH（和CD 19）有助于肿瘤抑制。我们还发现，通过检查BASH缺陷的抗DNA抗体敲入小鼠，自结合抗原受体的编辑显着依赖于BASH。因此，受体编辑在建立自身耐受性中的贡献被清楚地记录。BASH与Btk、PLCγ、Vav、Grb 2、HPK 1等信号分子相互作用，在BCR信号转导中具有重要意义。我们已经鉴定了与BASH的保守N-末端结构域结合的新蛋白，并将其命名为BNAS 1和BNAS 2。推测它们都是4倍膜跨蛋白，定位于内质网、高尔基体和核周区。利用基因靶向方法的功能研究目前正在进行中。少

Pre-B cell receptor (pre-BCR) signaling induces proliferative expansion of large pre-B cells and the following differentiation into small pre-B cells (pre-B cell transition), and inhibits V_H to DJ_H rearrangement of IgH locus (IgH allelic exclusion), the latter also accounting for counter-selection of pro-B cells expressing Dμ protein (Dμ selection). We have previously shown that a B-cell specific adaptor protein, BASH (or BLNK/SLP-65), which is critical for B-cell antigen receptor(BCR) signaling, is important, but not essential, for pre-B cell transition. In this study we have discovered a buck-up role in the pre-BCR signaling for CD19, a B-cell specific co-receptor for BCR. The pre-B cell transition was completely abolished and accumulation of large non-cycling, pre-BCR-expressing cells was augmented in BASH/CD19 double-mutant mice. However, IgH allelic exclusion was intact even in the double-mutant mice, while Dμ selection was abolished in BASH- and the double-mutant mice. Thus, di … More stinct signals are required for these events. In addition, these mice succumbed to pre-B cell leukemia, indicating BASH (and CD19) contributes to tumor suppression.We also found that editing of self-binding antigen receptors is significantly dependent on BASH, through examining anti-DNA-antibody knock-in mice deficient for BASH. Thus contribution of the receptor editing in the establishment of self-tolerance is clearly documented. In addition, BASH has turned out to be unnecessary for T-independent secondary and memory response, as well as affinity maturation of antibodies.BASH interacts with signaling molecules such as Btk, PLCγ, Vav, Grb2, HPK1, and the significance of such interactions in BCR signal transduction has been shown. We have identified novel proteins that bind to a conserved N-terminal domain of BASH, and termed them BNAS1 and BNAS2. They are both presumed to be a 4-times membrane-span protein and localize at endoplasmic reticulum, Golgi apparatus and peri-nuclear region. Functional studies utilizing gene targeting methodology are currently underway. Less