Pan Yonghua, Lin Meei-Hua, Tian Xiaolin, Cheng Hui-Teng, Gridley Thomas, Shen Jie, Kopan Raphael
Department of Molecular Biology and Pharmacology, Division of Dermatology, Washington University School of Medicine, Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Dev Cell. 2004 Nov;7(5):731-43. doi: 10.1016/j.devcel.2004.09.014.
The role of Notch signaling during skin development was analyzed using Msx2-Cre to create mosaic loss-of-function alleles with precise temporal and spatial resolution. We find that gamma-secretase is not involved in skin patterning or cell fate acquisition within the hair follicle. In its absence, however, inner root sheath cells fail to maintain their fates and by the end of the first growth phase, the epidermal differentiation program is activated in outer root sheath cells. This results in complete conversion of hair follicles to epidermal cysts that bears a striking resemblance to Nevus Comedonicus. Sebaceous glands also fail to form in gamma-secretase-deficient mice. Importantly, mice with compound loss of Notch genes in their skin phenocopy loss of gamma-secretase in all three lineages, demonstrating that Notch proteolysis accounts for the major signaling function of this enzyme in this organ and that both autonomous and nonautonomous Notch-dependent signals are involved.
利用Msx2-Cre以精确的时间和空间分辨率创建镶嵌功能缺失等位基因，分析Notch信号在皮肤发育过程中的作用。我们发现γ-分泌酶不参与毛囊内的皮肤模式形成或细胞命运获得。然而，在其缺失的情况下，内根鞘细胞无法维持其命运，到第一个生长阶段结束时，外根鞘细胞中表皮分化程序被激活。这导致毛囊完全转化为与黑头粉刺痣极为相似的表皮囊肿。皮脂腺在γ-分泌酶缺陷型小鼠中也无法形成。重要的是，皮肤中Notch基因复合缺失的小鼠在所有三个谱系中都表现出γ-分泌酶缺失的表型，这表明Notch蛋白水解作用是该酶在这个器官中的主要信号功能，并且自主和非自主的Notch依赖性信号都参与其中。
