Xu Shengli, Lee Koon-Guan, Huo Jianxin, Kurosaki Tomohiro, Lam Kong-Peng
Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institute, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673.
Blood. 2007 Apr 15;109(8):3377-84. doi: 10.1182/blood-2006-07-036418. Epub 2006 Dec 12.
Bruton tyrosine kinase (Btk) and phospholipase Cgamma2 (PLCgamma2) are 2 key molecules involved in B-cell receptor (BCR) signaling. Biochemical studies have placed them in a linear signaling pathway, with Btk acting upstream of PLCgamma2. Consistent with this, mice lacking either molecule display a leaky but similar block in B-cell development. Here, we generated Btk(-/-) PLCgamma2(-/-) mice and showed that combined deficiencies in Btk and PLCgamma2 severely arrested B lymphopoiesis at the large pre-B-cell stage. In contrast to either single mutant, Btk(-/-) PLCgamma2(-/-) pre-B cells expressed high levels of pre-BCR on their cell surfaces and exhibited reduced immunoglobulin light chain gene rearrangements. Pre-BCR-induced calcium signaling was also drastically compromised in Btk(-/-) PLCgamma2(-/-) pre-B cells compared with wild-type and single-mutant cells. Interestingly, immunoglobulin heavy chain allelic exclusion remained intact in the absence of Btk and PLCgamma2. Overall, our results suggest that Btk and PLCgamma2 have combinatorial roles in regulating pre-B cell differentiation.
布鲁顿酪氨酸激酶（Btk）和磷脂酶Cγ2（PLCγ2）是参与B细胞受体（BCR）信号传导的两个关键分子。生化研究已将它们置于线性信号通路中，Btk在PLCγ2的上游起作用。与此一致的是，缺乏这两种分子中的任何一种的小鼠在B细胞发育中表现出渗漏但相似的阻滞。在此，我们构建了Btk（-/-）PLCγ2（-/-）小鼠，并表明Btk和PLCγ2的联合缺陷在大前B细胞阶段严重阻滞了B淋巴细胞生成。与单一突变体不同，Btk（-/-）PLCγ2（-/-）前B细胞在其细胞表面高水平表达前BCR，并表现出免疫球蛋白轻链基因重排减少。与野生型和单一突变体细胞相比，Btk（-/-）PLCγ2（-/-）前B细胞中前BCR诱导的钙信号也受到严重损害。有趣的是，在没有Btk和PLCγ2的情况下，免疫球蛋白重链等位基因排斥仍然完整。总体而言，我们的结果表明Btk和PLCγ2在调节前B细胞分化中具有协同作用。
