Schlissel M S, Morrow T
Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD 21205.
J Immunol. 1994 Aug 15;153(4):1645-57.
The membrane-associated form of Ig heavy chain (mu) protein has been implicated as a critical regulator of B cell development. Mutant mice unable to produce the membrane form of mu protein fail to produce mature B cells. Splenic B cells from mice transgenic for a functionally rearranged Ig mu gene show a marked decrease in endogenous heavy chain gene rearrangement. We have analyzed the effects of a human mu transgene on the regulation of V(D)J recombination during B cell development in the mouse fetal liver. We found that mu transgenic and wild-type littermate mice begin kappa light chain gene rearrangement at the same time during development but the transgenic mice show a striking increase in the frequency of kappa gene rearrangement. The transgenic mice also show an increase in the levels of a germ-line kappa gene transcript known to be associated with kappa gene rearrangement. D-to-JH heavy chain gene rearrangement is unaffected throughout development by the presence of the mu transgene. Endogenous heavy chain gene V-to-DJH rearrangement occurs with similar frequency in transgenic and nontransgenic fetal livers during midgestation but is reduced in late gestation mu transgenic fetal liver. We show that this decrease in rearrangement is associated with a decrease in unrearranged VH gene transcription. Furthermore, we show that changes in the frequencies of rearranged kappa and mu genes are accompanied by changes in the frequencies of dsDNA breaks, a V(D)J recombination reaction intermediate associated with each of these loci. We propose that membrane-associated mu protein regulates B cell development by signaling a change in the pattern of unrearranged Ig gene transcriptional activity, thereby retargeting the V(D)J recombinase.
免疫球蛋白重链（μ）蛋白的膜相关形式被认为是B细胞发育的关键调节因子。无法产生μ蛋白膜形式的突变小鼠不能产生成熟的B细胞。转染了功能重排的免疫球蛋白μ基因的小鼠脾脏B细胞内源性重链基因重排显著减少。我们分析了人μ转基因对小鼠胎肝B细胞发育过程中V（D）J重组调控的影响。我们发现，μ转基因小鼠和野生型同窝小鼠在发育过程中同时开始κ轻链基因重排，但转基因小鼠κ基因重排频率显著增加。转基因小鼠中已知与κ基因重排相关的种系κ基因转录水平也有所增加。μ转基因的存在在整个发育过程中对重链基因D-JH重排没有影响。在妊娠中期，转基因和非转基因胎肝中内源性重链基因V-DJH重排频率相似，但在妊娠后期μ转基因胎肝中重排减少。我们发现这种重排减少与未重排的VH基因转录减少有关。此外，我们发现重排的κ和μ基因频率的变化伴随着双链DNA断裂频率的变化，双链DNA断裂是与这些基因座相关的V（D）J重组反应中间体。我们提出，膜相关μ蛋白通过发出未重排的免疫球蛋白基因转录活性模式变化的信号来调节B细胞发育，从而重新定位V（D）J重组酶。
