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

点击翻译按钮获取中文摘要

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.