Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice
Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice
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DOI：
10.1128/mcb.01871-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Spyropoulos, Dernetri D.
中科院分区：
文献类型：
--
作者：
Higuchi, Tsukasa;Bartel, Frank O.;Spyropoulos, Dernetri D.
Ets1 是 Ets 转录因子家族的成员。外显子 VII 的选择性剪接产生两种天然存在的蛋白质亚型：全长 Ets1 (p51-Ets1) 和 Ets1(Delta VII) (p42-Ets1)。这些亚型在蛋白质-蛋白质相互作用、DNA 结合动力学和转录靶标特异性方面具有重要区别。小鼠中两种 Ets1 同工型的破坏会导致可检测的 NK 和 NKT 细胞活性丧失以及 B 和 T 淋巴细胞缺陷。我们生成了仅表达 Ets1(Delta VII) 同种型的小鼠。与野生型相比，Ets1(Delta VII) 纯合小鼠不表达 p51-Ets1，但 p42-Ets1 蛋白水平升高，并表现出围产期死亡率增加、胸腺肿大和外周淋巴细胞减少。纯合子的胸腺和脾脏增殖均增加，而胸腺细胞凋亡减少，脾脏细胞凋亡增加。观察到CD8(+)和CD8(+)CD4(+)胸腺细胞显着升高。淋巴细胞（CD19（+）、CD4（+）和CD8（+））减少是脾细胞结构减少、记忆细胞减少以及维持外周淋巴细胞稳态增殖失败的主要原因。总的来说，Ets1(Delta VII) 突变体表现出与 p16(Ink4a) p27(Kip1) 和 CD44 失调相关的淋巴细胞成熟缺陷。因此，Ets1亚型差异调节的平衡代表了控制淋巴成熟和稳态的潜在机制。
Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1(Delta VII) (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics, and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1(Delta VII) isoform. Ets1(Delta VII) homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8(+) and CD8(+)CD4(+) thymocytes were observed. Lymphoid cell (CD19(+), CD4(+), and CD8(+)) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1(Delta VII) mutants demonstrate lymphocyte maturation defects associated with misregulation of p16(Ink4a) p27(Kip1), and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.