Oro Anthony E, Higgins Kay
Program in Epithelial Biology, CCSR 2145c, 269 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305, USA.
Dev Biol. 2003 Mar 15;255(2):238-48. doi: 10.1016/s0012-1606(02)00042-8.
Proper patterning of self-renewing organs, like the hair follicle, requires exquisite regulation of growth signals. Sonic hedgehog (Shh) signaling in skin controls the growth and morphogenesis of hair follicle epithelium in part through regulating the Gli transcription factors. While ectopic induction of Shh target genes leads to hair follicle tumors, such as basal cell carcinomas, how Shh signaling normally functions during the cyclic process of hair development is unknown. Here, we show that, during the hair cycle, Shh expression and the ability of skin cells to respond to Shh signaling is spatially and temporally regulated. Induction of Shh target genes normally occurs only in the anagen hair follicle in response to expression of Shh. However, in patched1 heterozygous mice, putative tumor precursors form with concomitant induction of Shh target gene transcription only during anagen in follicular and interfollicular keratinocytes. Ectopic production of Gli1 accumulates Gli protein and induces Shh target genes and epithelial tumors at anagen but not other stages, pointing to a restricted competence occurring at the level of Gli protein accumulation. Delivery and reception of growth signals among multipotent cells are restricted in time and space to facilitate cyclic pattern formation.
自我更新器官（如毛囊）的正常模式形成需要对生长信号进行精确调控。皮肤中的音猬因子（Shh）信号传导部分通过调节Gli转录因子来控制毛囊上皮的生长和形态发生。虽然Shh靶基因的异位诱导会导致毛囊肿瘤，如基底细胞癌，但在毛发发育的循环过程中Shh信号传导通常如何发挥作用尚不清楚。在这里，我们表明，在毛发周期中，Shh的表达以及皮肤细胞对Shh信号作出反应的能力在空间和时间上受到调控。Shh靶基因的诱导通常仅在生长期毛囊中响应Shh的表达而发生。然而，在patched1杂合小鼠中，假定的肿瘤前体仅在生长期的毛囊和毛囊间角质形成细胞中伴随Shh靶基因转录的诱导而形成。Gli1的异位产生会积累Gli蛋白，并在生长期而非其他阶段诱导Shh靶基因和上皮肿瘤，这表明在Gli蛋白积累水平存在有限的反应能力。多能细胞之间生长信号的传递和接收在时间和空间上受到限制，以促进循环模式的形成。
