Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division.
Early B Cell Progenitors Deficient for GON4L Fail To Differentiate Due to a Block in Mitotic Cell Division.
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DOI：
10.4049/jimmunol.1602054
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发表时间：
2017-05-15
期刊：
影响因子：
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通讯作者：
Colgan JD
中科院分区：
文献类型：
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作者：
Barr JY;Goodfellow RX;Colgan DF;Colgan JD
Justy 突变小鼠的 B 细胞发育因前体 mRNA 剪接缺陷而受阻，该缺陷会耗尽 B 细胞祖细胞中的 GON4 样蛋白 (GON4L)。遗传和生化研究表明 GON4L 是一种协调细胞分裂与分化的转录调节因子，但其在 B 细胞发育中的作用尚不清楚。为了了解 GON4L 的功能，我们对 Justy 小鼠 GON4L 缺陷的 B 细胞祖细胞中的 B 细胞分化、细胞周期控制和有丝分裂基因表达进行了表征。我们发现这些细胞建立了指导 B 细胞发育和增殖的转录因子网络的关键方面，并重新排列了免疫球蛋白重链基因座。然而，尽管 IL-7 信号传导完整，但 GON4L 缺陷的前 B 细胞阶段前体未能经历特征性的 IL-7 依赖性增殖爆发。这些细胞也未能上调有丝分裂所需的基因，包括编码 G1/S 细胞周期蛋白 D3 和 E2F 转录因子及其靶标的基因。此外，GON4L 缺陷的 B 细胞祖细胞在 DNA 合成和 G1/S 转变过程中表现出缺陷，含有片段化 DNA 并经历细胞凋亡。这些表型没有被促生存因子的转基因表达所抑制。然而，细胞周期蛋白 D3 或其他 G1/S 转变调节因子的转基因表达恢复了 Justy 祖细胞的前 B 细胞发育，表明 GON4L 在细胞周期开始时发挥作用。总之，我们的研究结果表明 GON4L 对于 B 细胞发育早期阶段的细胞周期进展和分裂至关重要。
B cell development in Justy mutant mice is blocked due to a pre-mRNA splicing defect that depletes the protein GON4-like (GON4L) in B cell progenitors. Genetic and biochemical studies have suggested GON4L is a transcriptional regulator that coordinates cell division with differentiation, but its role in B cell development is unknown. To understand the function of GON4L, we characterized B cell differentiation, cell cycle control, and mitotic gene expression in GON4L-deficient B cell progenitors from Justy mice. We found that these cells established key aspects of the transcription factor network that guides B cell development and proliferation and rearranged the immunoglobulin heavy chain gene locus. However, despite intact IL-7 signaling, GON4L-deficient pro-B cell stage precursors failed to undergo a characteristic IL-7-dependent proliferative burst. These cells also failed to upregulate genes required for mitotic division, including those encoding the G1/S cyclin D3 and E2F transcription factors and their targets. Additionally, GON4L-deficient B cell progenitors displayed defects in DNA synthesis and passage through the G1/S transition, contained fragmented DNA and underwent apoptosis. These phenotypes were not suppressed by transgenic expression of pro-survival factors. However, transgenic expression of cyclin D3 or other regulators of the G1/S transition restored pro-B cell development from Justy progenitor cells, suggesting GON4L acts at the beginning of the cell cycle. Together, our findings indicate GON4L is essential for cell cycle progression and division during the early stages of B cell development.