Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), Station 19, 1015 Lausanne, Switzerland.
Immunity. 2010 Nov 24;33(5):671-84. doi: 10.1016/j.immuni.2010.11.014.
Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.
尽管经典的 Notch 信号通路调节包括 T 细胞和边缘区 B 细胞命运特化在内的多种造血谱系决定，但 Notch 功能的下游分子介质在很大程度上仍是未知的。我们在这里表明，在成年鼠骨髓（BM）细胞中条件性失活 Hes1（一种特征明确的 Notch 靶基因），严重损害了 T 细胞的发育，而不影响其他 Notch 依赖性造血谱系，如边缘区 B 细胞。竞争性混合 BM 嵌合体、胸腺内转移实验以及在 Delta-like 表达基质细胞上培养 BM 祖细胞进一步表明，Hes1 是 T 细胞谱系决定所必需的，但对于 Notch 依赖性胸腺细胞成熟，从β选择检查点之前到之后都是可有可无的。此外，我们的数据强烈表明 Hes1 对于 Notch 诱导的 T 细胞急性淋巴细胞白血病的发展和维持是必不可少的。总之，我们的研究确定 Hes1 是造血系统中经典 Notch 信号通路的关键但具有上下文依赖性的介质。
