Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
复制标题
DOI：
10.1073/pnas.0601188103
复制
发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Rothenberg, Ellen V.
中科院分区：
文献类型：
--
作者：
Franco, Christopher B.;Scripture-Adams, Deirdre D.;Rothenberg, Ellen V.
PU1对小鼠T细胞发育的早期阶段是必不可少的，但如果有结构性表达，则会拮抗它。其中涉及两种可分离的机制：衰减和转移。PU.1的异常表达通过阻断必要的T细胞转录因子、信号分子和RAG基因的表达来抑制亲T细胞的生存、增殖和通过β-选择，而重排的T细胞抗原受体转基因表达不能挽救这些表达。然而，Bcl2转基因细胞不受这种衰减的影响，甚至可能经历β-选择，正如在OP9-DL1和OP9对照培养中PU.1转导具有分化的Bcl2转基因胎儿胸腺细胞亚群所表明的那样。PU.1在这些细胞中的表达结果取决于Notch/Delta信号转导。PU.1可以通过多基因调控改变有效地将胸腺细胞转向髓样状态，但Notch/Delta信号转导被否决。基因表达分析区分了一组对PU.1和Notch/Delta信号有不同组合反应的关键T细胞系调控基因，这表明在分流过程中抑制E蛋白、Myb和/或Gfi1(生长因子独立1)特别重要。然而，Notch信号只保护在Thy-1和CD25上调后经历T细胞谱系指定的细胞的转移。结果表明，在T细胞前体中，Notch/Delta信号通常在从T谱系指定到承诺的过程中调节和引导PU1的转录活动。
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.