Dionne Christopher J, Tse Kevin Y, Weiss Angela H, Franco Christopher B, Wiest David L, Anderson Michele K, Rothenberg Ellen V
Division of Biology 156-29, California Institute of Technology, Pasadena, 91125 USA.
Dev Biol. 2005 Apr 15;280(2):448-66. doi: 10.1016/j.ydbio.2005.01.027.
Specification of mammalian T lymphocytes involves prolonged developmental plasticity even after lineage-specific gene expression begins. Expression of transcription factor PU.1 may maintain some myeloid-like developmental alternatives until commitment. Commitment could reflect PU.1 shutoff, resistance to PU.1 effects, and/or imposition of a suicide penalty for diversion. Here, we describe subclones from the SCID.adh murine thymic lymphoma, adh.2C2 and adh.6D4, that represent a new tool for probing these mechanisms. PU.1 can induce many adh.2C2 cells to undergo diversion to a myeloid-like phenotype, in an all-or-none fashion with multiple, coordinate gene expression changes; adh.6D4 cells resist diversion, and most die. Diversion depends on the PU.1 Ets domain but not on known interactions in the PEST or Q-rich domains, although the Q-rich domain enhances diversion frequency. Protein kinase C/MAP kinase stimulation can make adh.6D4 cells permissive for diversion without protecting from suicide. These results show distinct roles for regulated cell death and another stimulation-sensitive function that establishes a threshold for diversion competence. PU.1 also diverts normal T-cell precursors from wild type or Bcl2-transgenic mice to a myeloid-like phenotype, upon transduction in short-term culture. The adh.2C2 and adh.6D4 clones thus provide an accessible system for defining mechanisms controlling developmental plasticity in early T-cell development.
哺乳动物T淋巴细胞的特化涉及长期的发育可塑性,即使在谱系特异性基因表达开始之后也是如此。转录因子PU.1的表达可能会维持一些髓样样的发育选择,直到细胞定型。细胞定型可能反映了PU.1的关闭、对PU.1作用的抗性和/或对分化施加的自杀惩罚。在这里,我们描述了来自SCID.adh小鼠胸腺淋巴瘤的亚克隆adh.2C2和adh.6D4,它们代表了一种探索这些机制的新工具。PU.1可以诱导许多adh.2C2细胞以全或无的方式转变为髓样样表型,并伴随着多个协同的基因表达变化;adh.6D4细胞抵抗转变,并且大多数细胞死亡。细胞转变依赖于PU.1的Ets结构域,但不依赖于PEST或富含Q的结构域中的已知相互作用,尽管富含Q的结构域会提高细胞转变频率。蛋白激酶C/丝裂原活化蛋白激酶刺激可以使adh.6D4细胞允许细胞转变,但不能防止细胞自杀。这些结果表明,调节性细胞死亡和另一种刺激敏感性功能在建立细胞转变能力阈值方面具有不同的作用。在短期培养中转导时,PU.1还会将野生型或Bcl2转基因小鼠的正常T细胞前体转变为髓样样表型。因此,adh.2C2和adh.6D4克隆提供了一个易于研究的系统,用于确定控制早期T细胞发育中发育可塑性的机制。