Canonical Notch signaling functions as a commitment switch in the epidermal lineage
Canonical Notch signaling functions as a commitment switch in the epidermal lineage
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DOI：
10.1101/gad.1477606
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发表时间：
2006-11-01
影响因子：
10.5
通讯作者：
Fuchs, Elaine
中科院分区：
文献类型：
--
作者：
Blanpain, Cedric;Lowry, William E.;Fuchs, Elaine
哺乳动物表皮由增殖祖细胞的基底层组成，其产生多个分化层以提供覆盖皮肤表面的防水包膜。为了实现这一点，祖细胞必须从基底层分离，向上移动，并执行由三个不同阶段组成的终末分化程序：棘层，颗粒层和角质层。Notch信号转导与分化的晚期阶段有关，但承诺开关仍然未知。在这里，我们显示与损失和增益的功能研究，积极的Notch胞内结构域（NICD）和其专性的典型信号合作伙伴RBP-J在基底/基底上交界处的行为，以诱导棘和下调基础的命运。棘层在RBP-J条件无效表皮中不存在，并且当Notch 1信号传导在表皮中转基因升高时扩展。我们表明，RBP-J是必不可少的介导棘基因激活和基础基因的镇压。相反，NICD/RBP-J靶基因Hes 1在棘层中表达，介导棘基因诱导，但不介导基础基因抑制。这些数据揭示了RBP-J和Notch在表皮细胞终末分化中的早期作用，并揭示了棘基因诱导是由Hes 1依赖性机制介导的，而基础基因抑制独立于Hes 1发生。
Mammalian epidermis consists of a basal layer of proliferative progenitors that gives rise to multiple differentiating layers to provide a waterproof envelope covering the skin surface. To accomplish this, progenitor cells must detach from the basal layer, move upward, and execute a terminal differentiation program consisting of three distinct stages: spinous, granular layer, and stratum corneum. Notch signaling has been implicated in late stages of differentiation, but the commitment switch remains unknown. Here we show with loss and gain-of-function studies that active Notch intracellular domain (NICD) and its obligate canonical signaling partner RBP-J act at the basal/suprabasal juncture to induce spinous and down-regulate basal fate. Spinous layers are absent in RBP-J conditional null epidermis and expanded when Notch1 signaling is elevated transgenically in epidermis. We show that RBP-J is essential for mediating both spinous gene activation and basal gene repression. In contrast, the NICD/RBP-J target gene Hes1 is expressed in spinous layers and mediates spinous gene induction but not basal gene repression. These data uncover an early role for RBP-J and Notch in commitment of epidermal cells to terminally differentiate and reveal that spinous gene induction is mediated by a Hes1-dependent mechanism, while basal gene repression occurs independently of Hes1.