School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Korea.
Nucleic Acids Res. 2021 Jun 4;49(10):5760-5778. doi: 10.1093/nar/gkab389.
Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.
可变剪接是生成多种转录本的关键步骤，从而极大地增加了蛋白质组的多样性。因此，大多数可变剪接因子敲除模型的一个共同特征是致死性。然而，在生理环境中，关于谱系特异性可变剪接调控因子的了解甚少。在这里，我们报告 NSrp70 选择性地在发育中的胸腺细胞中表达，在双阳性 (DP) 阶段表达最高。全局剪接和转录谱分析表明，NSrp70 通过控制各种 RNA 剪接因子的可变剪接来调控胸腺细胞的细胞周期和存活，包括致癌剪接因子 SRSF1。使用 CD4Cre 对 Nsrp1（NSrp70-cKO）进行条件敲除会导致 T 细胞成熟为单阳性胸腺细胞的严重缺陷，这是由于 TCR 信号不足以及细胞生长和死亡失控。小鼠表现出严重的外周淋巴细胞减少症，无法最佳地控制肿瘤生长。这项研究建立了一个模型，以解决淋巴谱系特异性可变剪接因子 NSrp70 在胸腺 T 细胞发育途径中的功能。
