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Essential role of transcriptional regulator Hesl in the early development of T cells.

转录调节因子 Hesl 在 T 细胞早期发育中的重要作用。

基本信息

批准号：
10670300
负责人：
HATTORI Masakazu
金额：
$ 2.11万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670300/
关键词：
Hesl bHLH T cell RAG2 Notchl thymus HES1 T細胞増殖制御ストローマ細胞 Pre T細胞 T細胞初期分化 double negative TCR非依存性増殖

项目摘要

T cells undergo multiple of proliferation and differentiation in the thymus before final maturation, in which a number of transcriptional regulators are shown to control the distinct steps by regulating specific sets of gene activation. Hes 1, a mammalian counterpart of Drosophila Hairy and Enhancer of split, is a member of basic helix-loop-helix (bHLH) transcriptional regulators and expressed in the developing nervous tissues and thymus in normal embryo. Fetus of Hes 1 deficient mice were found to exhibit severe thymus dysplasia in addition of the anomalous development of nervous system. Transfer experiments of fetal liver into RAG2 deficient mice indicate that Hes 1 (-1-) fetal liver cells mostly totally failed to repopulate the thymus while B cells and other hematopoietic cells were reconstituted normally. Detailed analysis revealed that the differentiation of T cells in thymus from Hes 1 (-1-) stem cells was arrested at the earliest recognizable stage, CD4ィイD1-ィエD1CD8ィイD1-ィエD1CD44ィイD1+ィエD1CD25ィイD1-ィエD1 with no evidence of TCR gene rearrangement. The results clearly indicate that Hes 1 is indispensably required cell-autonomously for the earliest expansion of pro-T cells in the thymus. Hes 1 is shown to be at the down-stream of Notch signal pathway, and it was reported by other group that conditional Notch 1 gene targeting in adult mice show similar specific effects on thymocyte development. Using appropriate cell systems, we are currently studying the molecular mechanisms, in which Hesl controls the proliferation and differentiation at the specificstages of T cell development.

T细胞在最终成熟之前在胸腺中经历多次增殖和分化，其中许多转录调节因子被证明通过调节特定的基因激活集来控制不同的步骤。Hes 1是果蝇Hairy和分裂增强子（Enhancer of split）在哺乳动物中的对应物，是碱性螺旋-环-螺旋（bHLH）转录调节因子的成员，在正常胚胎发育的神经组织和胸腺中表达。发现Hes 1基因缺陷小鼠的胎儿除了神经系统发育异常外，还表现出严重的胸腺发育不良。胎肝移植到RAG 2缺陷小鼠的实验表明，Hes 1（-1-）胎肝细胞大多数完全不能重建胸腺，而B细胞和其他造血细胞正常重建。进一步分析表明，Hes 1（-1-）干细胞在胸腺中的T细胞分化停滞在最早可识别的阶段，为CD 4 + CD 1-CD 1CD 8 + CD 1-CD 1CD 44 + CD 1CD 25 + CD 1-CD 1CD 1，无TCR基因重排的证据。结果清楚地表明，Hes 1是胸腺中pro-T细胞最早扩增所必需的细胞自主性。Hes 1位于Notch信号通路的下游，其他研究组也报道了条件性Notch 1基因靶向对成年小鼠胸腺细胞发育的特异性影响。目前，我们正在利用合适的细胞系统研究Hesl在T细胞发育的特定阶段控制增殖和分化的分子机制。