B cell development is linked to successful V(D)J recombination, allowing B cell receptor expression and ultimately antibody secretion for adaptive immunity. Germline noncoding RNAs (ncRNAs) are produced at immunoglobulin (Ig) loci during V(D)J recombination, but their function and posttranscriptional regulation are incompletely understood. Patients with trichohepatoenteric syndrome, characterized by RNA exosome pathway component mutations, exhibit lymphopenia, thus demonstrating the importance of ncRNA surveillance in B cell development in humans. To understand the role of RNA exosome in early B cell development in greater detail, we generated mouse models harboring a B cell–specific cre allele ( Mb1 cre ), coupled to conditional inversion-deletion alleles of one RNA exosome core component ( Exosc3 ) or RNase catalytic subunits ( Exosc10 or Dis3 ). We noticed increased expression of RNA exosome subunits during V(D)J recombination, whereas a B cell developmental blockade at the pro–B cell stage was observed in the different knockout mice, overlapping with a lack of productive rearrangements of VDJ genes at the Ig heavy chain ( Igh ). This unsuccessful recombination prevented differentiation into pre–B cells, with accumulation of ncRNAs and up-regulation of the p53 pathway. Introduction of a prearranged Igh VDJ allele partly rescued the pre–B cell population in Dis3 -deficient cells, although V-J recombination defects were observed at Ig light chain kappa ( Ig κ), preventing subsequent B cell development. These observations demonstrated that the RNA exosome complex is important for Igh and Ig κ recombination and establish the relevance of RNA processing for optimal diversification at these loci during B cell development.

中文翻译：

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RNA外泌体通过非编码RNA加工机制驱动早期B细胞发育

B 细胞发育与成功的 V(D)J 重组有关，允许 B 细胞受体表达并最终分泌抗体以实现适应性免疫。生殖系非编码 RNA (ncRNA) 在 V(D)J 重组过程中在免疫球蛋白 (Ig) 基因座上产生，但它们的功能和转录后调控尚不完全清楚。以 RNA 外泌体通路成分突变为特征的毛肝肠综合征患者表现出淋巴细胞减少，从而证明了 ncRNA 监测在人类 B 细胞发育中的重要性。为了更详细地了解 RNA 外泌体在早期 B 细胞发育中的作用，我们生成了具有 B 细胞特异性的小鼠模型cre等位基因（mb1cre ），与一种RNA外泌体核心成分的条件倒位缺失等位基因偶联（Exosc3) 或 RNase 催化亚基 (Exosc10或者DIS3）。我们注意到在 V(D)J 重组过程中 RNA 外泌体亚基的表达增加，而在不同的敲除小鼠中观察到前 B 细胞阶段的 B 细胞发育阻滞，与 VDJ 基因在免疫球蛋白重链（高）。这种不成功的重组阻止了前 B 细胞的分化，导致 ncRNA 的积累和 p53 通路的上调。预先安排的介绍高VDJ 等位基因部分挽救了DIS3-缺陷细胞，尽管在免疫球蛋白轻链 kappa (免疫球蛋白κ)，防止随后的 B 细胞发育。这些观察结果表明，RNA 外泌体复合物对于高和免疫球蛋白κ 重组并建立 RNA 加工与 B 细胞发育过程中这些基因座的最佳多样化的相关性。