Expression profiling of immature thymocytes revealed a novel homeobox gene that regulates double-negative thymocyte development
Expression profiling of immature thymocytes revealed a novel homeobox gene that regulates double-negative thymocyte development
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DOI：
10.4049/jimmunol.179.8.5335
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
--
作者：
Kawazu, Masahito;Yamamoto, Go;Ogawa, Seishi
CD 4/CD 8双阴性（DN）胸腺细胞的胸腺内发育可以通过明确的胸腺细胞时序亚群来追踪，并且是基因表达谱分析的理想靶点，以阐明成熟T细胞产生的遗传基础，通过基因表达谱研究未成熟胸腺细胞的分化。在这项研究中，我们表明，小鼠DN胸腺细胞的发展主要是受抑制，而不是诱导活动的translantine，在未成熟的胸腺细胞的谱系混杂基因表达下调，在其分化。基因的功能定位显示共同的时间表达谱牵连以前未知的基因调控，可能是相关的早期胸腺细胞的发展。少数基因在DN胸腺细胞的CD 44（低）CD 25（+）亚群中瞬时表达，从中我们鉴定了一种新的同源框基因Duxl，其表达受Runx 1上调。Duxl促进DN胸腺细胞中从CD 44（高）CD 25（+）向CD 44（低）CD 25（+）的转变，而Duxl的组成型表达抑制TCR β链的表达并导致β选择受损和CD 4/CD 8双阳性胸腺细胞的产生大大减少，表明其在DN胸腺细胞发育中的关键作用。
Intrathymic development of CD4/CD8 double-negative (DN) thymocytes can be tracked by well-defined chronological subsets of thymocytes, and is an ideal target of gene expression profiling analysis to clarify the genetic basis of mature T cell production, by which differentiation of immature thymocytes is investigated in terms of gene expression profiles. In this study, we show that development of murine DN thymocytes is predominantly regulated by largely repressive rather than inductive activities of transcriptions, where lineage-promiscuous gene expression in immature thymocytes is down-regulated during their differentiation. Functional mapping of genes showing common temporal expression profiles implicates previously uncharacterized gene regulations that may be relevant to early thymocytes development. A small minority of genes is transiently expressed in the CD44(low)CD25(+) subset of DN thymocytes, from which we identified a novel homeobox gene, Duxl, whose expression is up-regulated by Runx1. Duxl promotes the transition from CD44(high) CD25(+) to CD44(low)CD25(+) in DN thymocytes, while constitutive expression of Duxl inhibits expression of TCR beta-chains and leads to impaired beta selection and greatly reduced production of CD4/CD8 double-positive thymocytes, indicating its critical roles in DN thymocyte development.