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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
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Notch/Delta signaling constrains reengineering of pro-T cells by PU.1

机译：Notch / Delta信号通过PU.1限制pro-T细胞的再造。

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摘要

PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through beta-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo beta-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment.
机译：PU.1对于小鼠T细胞发育的早期阶段是必不可少的，但是如果组成型表达，它会拮抗它。涉及两个可分离的机制：衰减和转移。失调的PU.1表达通过阻断必需的T细胞转录因子，信号分子和Rag基因表达而抑制了pro-T细胞的存活，增殖和通过β选择的传递，而重排的T细胞抗原受体转基因的表达无法挽救。但是，Bcl2转基因细胞受到这种衰减的保护，甚至可能经过β选择，如PU.1所示，Bcl2转基因胎儿胸腺细胞的确定子集在OP9-DL1和OP9对照培养物中具有分化。这些细胞中PU.1表达的结果取决于Notch / Delta信号传导。 PU.1可以有效地将胸腺细胞转移到具有多基因调节变化的髓样状态，但是Notch / Delta信号转导否决权。基因表达分析区分了关键的T谱系调控基因集，这些基因对PU.1和Notch / Delta信号具有不同的组合响应，这表明抑制转移中的E蛋白，Myb和/或Gfi1（生长因子独立性1）特别重要。但是，Notch信号传导仅能防止Thy-1和CD25上调后经历T谱系指定的细胞转移。结果表明，在T细胞前体中，Notch / Delta信号传导通常在从T谱系指定到承诺的阶段中调节和引导PU.1转录活性。

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