Lindner Silke E, Lohmüller Michael, Kotkamp Bianka, Schuler Fabian, Knust Zeynep, Villunger Andreas, Herzog Sebastian
Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
EMBO Rep. 2017 Sep;18(9):1604-1617. doi: 10.15252/embr.201643735. Epub 2017 Jul 13.
Precursor B lymphocytes expand upon expression of a pre-B cell receptor (pre-BCR), but then transit into a resting state in which immunoglobulin light chain gene recombination is initiated. This bi-phasic sequence is orchestrated by the IL-7 receptor (IL-7R) and pre-BCR signaling, respectively, but little is known about microRNAs fine-tuning these events. Here, we show that pre-B cells lacking miR-15 family functions exhibit prolonged proliferation due to aberrant expression of the target genes cyclin E1 and D3. As a consequence, they fail to trigger the transcriptional reprogramming normally accompanying their differentiation, resulting in a developmental block at the pre-B cell stage. Intriguingly, our data indicate that the miR-15 family is suppressed by both IL-7R and pre-BCR signaling, suggesting it is actively integrated into the regulatory circuits of developing B cells. These findings identify the miR-15 family as a novel element required to promote the switch from pre-B cell proliferation to differentiation.
前体B淋巴细胞在表达前B细胞受体（pre-BCR）时会扩增，但随后会进入静止状态，在此状态下免疫球蛋白轻链基因重组开始。这种双相序列分别由白细胞介素-7受体（IL-7R）和前BCR信号传导编排，但关于微调这些事件的微小RNA知之甚少。在这里，我们表明缺乏miR-15家族功能的前B细胞由于靶基因细胞周期蛋白E1和D3的异常表达而表现出延长的增殖。因此，它们无法触发通常伴随其分化的转录重编程，导致在前B细胞阶段出现发育阻滞。有趣的是，我们的数据表明miR-15家族受到IL-7R和前BCR信号传导的抑制，这表明它被积极整合到发育中的B细胞的调节回路中。这些发现确定miR-15家族是促进从前B细胞增殖向分化转变所需的新元件。
